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Cancer Genetics Risk Assessment and Counseling (PDQ®)

Last modified: 2013-07-23
Last downloaded: Tuesday, September 03, 2013

Introduction

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer. These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify families who may benefit from a referral to genetic counseling. The PDQ cancer genetics information summaries on breast, ovarian, colorectal, prostate, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.

The following are features that suggest hereditary cancer:

  • Unusually early age of cancer onset (e.g., premenopausal breast cancer).
  • Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
  • Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
  • Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and sisters with breast cancer).
  • Cancers occurring in multiple generations of a family (i.e., autosomal dominant inheritance).
  • Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, or duodenal cancer).
  • Unusual presentation of cancer (e.g., male breast cancer).
  • Uncommon tumor histology (e.g., medullary thyroid carcinoma).
  • Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
  • Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and BRCA1/BRCA2mutations).

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

  • An individual's personal history (including ethnicity) and/or family history is suspicious for a genetic predisposition to cancer.
  • The genetic test has sufficient sensitivity and specificity to be interpreted.
  • The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk in family members.

A candidate for genetic testing receives genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition. Genetic education and counseling gives an individual time to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.


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Cancer Risk Assessment and Counseling

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions.

Several professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process. Examples of these organizations include the following:

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information. Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

Genetic Counseling

Genetic counseling has been defined by the American Society of Human Genetics as “a communication process that deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family." The process involves an attempt by one or more appropriately trained persons to help the individual or family do the following:

In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including integration of the following:

  • Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
  • Education about inheritance, testing, management, prevention, resources, and research.
  • Counseling to promote informed choices and adaptation to the risk or condition.

Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity; and other relevant background characteristics. The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past. Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information. Findings from a psychosocial assessment can be used to help guide the direction of the counseling session. An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for mutation carriers and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals. Uptake of genetic counseling services among those referred varies based on the cancer syndrome. For example, hereditary breast and ovarian cancer genetic referral uptake is moderate (about 30%). Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services by at-risk women). Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.

Cancer Risk Assessment Counseling

The scope of genetic counseling practice has expanded over the past several years to address risk assessment and genetic testing for hereditary cancer predisposition. Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training. Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services and is available on the National Cancer Institute's Web site.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported. Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines, with the exception of genetic specialists. Knowledge deficits in hereditary cancer syndromes and concerns about genetic discrimination influence provider referral patterns for genetic counseling. A study of 1,181 California physicians and nurse practitioners examined knowledge gaps and perceptions about cancer genetic testing, genetic discrimination, and genetic nondiscrimination laws. Factors associated with having referred patients for cancer genetic counseling included having a more positive attitude toward genetic testing and a greater knowledge of nondiscrimination laws. Respondents who believed that genetic discrimination exists with regard to health insurance, and those who saw a higher number of underserved patients in their practice, were less likely to have referred patients for cancer genetic counseling. In a single-institution study, a retrospective chart review was conducted over a 10-year period to determine the genetic counseling referral rate for patients with ovarian, fallopian tube, or primary peritoneal cancers who were also at high risk of BRCA1/BRCA2 mutations. Results showed that referral rates increased from 12% in 1997 to 48% in 2007; however, the latter referral rate was deemed suboptimal because the majority of at-risk patients had not been referred for counseling.

The National Coalition for Health Professional Education in Genetics (NCHPEG) was established in 1996 to enhance the level of general professional education about genetics. NCHPEG has published and updated core competencies for all health professionals. Building on this work, individual health professions, such as nursing and physician assistants, have developed and published core competencies specific to their profession. A number of other organizations have also published professional guidelines, scopes, and standards of practice.

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing. Additionally, computer programs and Web sites designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.

Some studies of patient satisfaction with cancer genetic counseling services have been published. For example, one survey of individuals who participated in a cancer genetics program in its inaugural year reported that the clinical services met the needs and expectations of most people. Patients reported that the best parts of the experience were simply having a chance to talk to someone about cancer concerns, having personalized summary letters and family pedigrees, learning that cancer risk was lower than expected, or realizing that one had been justified in suspecting the inheritance of cancer in one’s family.

Several studies have since shown that the majority of individuals are satisfied with their genetic counseling experience. However, one study of 61 women participating in a BRCA1/2 genetic testing program found that satisfaction with genetic counseling was influenced by psychological variables including optimism, family functioning, and general and cancer-specific distress.

A meta-analysis of several controlled studies showed that outcomes of genetic counseling included improvement in cancer genetic knowledge (pooled short-term difference – 0.70 U, 95% confidence interval, 0.15–1.26 U). Overall, no long-term increases in general anxiety, cancer-specific worry, distress, or depression were detected as a consequence of genetic counseling. However, the impact of genetic counseling on risk perception is less clear, with some studies reporting no change in risk perception while others report significant differences before and after counseling.


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Components of the Risk Assessment Process

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available, such as the National Comprehensive Cancer Network Practice Guidelines for Genetic/Familial High Risk Assessment: Breast and Ovarian Cancer. Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

  • A detailed, multifaceted assessment.
  • A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
  • Education and counseling.
  • Establishment of a cancer risk management plan.

Assessment

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

Psychosocial assessment

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

  • Motivations for seeking cancer risk assessment.
  • Beliefs about the causes of cancer.
  • Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
  • The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
  • Cultural, religious, and socioeconomic background.
  • General psychological issues, such as depression or anxiety.
  • Coping mechanisms.
  • Support systems.

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to, or in lieu of, testing.

One study has shown that the addition of a colored ecogenetic relationship map (CEGRM) to the psychosocial assessment is feasible for assessing the social milieu in which an individual resides. The CEGRM is a psychosocial assessment tool that expands the family pedigree to include a family systems genogram and ecomap.

Education

Assessing the concept of personal cancer risk and its relationship to genetics is complex and not completely understood. However, the evidence continues to accumulate that a set of evolving factors influences a person’s concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. This assessment includes the following:

  • Experiential and empathetic knowledge.
  • People's beliefs regarding the basis for the occurrence of cancer in themselves and/or their relatives.
  • Sources of information and inaccuracies and/or misperceptions.
  • Literacy level, including health and numeracy.
  • Personal theories of inheritance.
  • Patterns of decision making (deliberate vs. experiential).

A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.

Risk perception

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individual’s knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individual’s knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media. This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis. Additionally, individuals may have beliefs about how genetic susceptibility works in their family. For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related mutation. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals’ receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk. As such, individuals’ beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individual’s decision to participate in counseling, despite the fact that perceived risk often varies substantially from statistical risk estimates.

Clinical Evaluation

Personal health history

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

  • Current age.
  • Race and ethnicity.
  • History of benign or malignant tumors, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
  • Environmental exposures.
  • Diet and exercise practices.
  • Complementary and alternative medicine practices.
  • Past and current alcohol intake and tobacco use.
  • Screening practices and date of last screening exams, including imaging and/or physical examinations.

For consultands with a history of cancer, additional information collected includes the following:

  • Site of primary tumor.
  • Age at diagnosis.
  • Tumor pathology.
  • Treatment (e.g., surgery, chemotherapy, and radiation therapy).
  • Bilaterality of disease, if applicable.
  • Current surveillance plan.

Physical examination

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

Family history

Documenting the family history

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment. Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information and that the use of these questionnaires is an acceptable and understandable family history collection method. However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required. Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.Factors suggesting inherited cancer risk were previously discussed.

Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.

Standards of pedigree nomenclature have been established. Refer to Figure 1 for common pedigree symbols.

Documentation of a family cancer history typically includes the following:

  • A minimum of three generations of relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.
  • Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific mutations in some genes are known to occur with increased frequency in some populations (founder effect).
  • Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
  • Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when available.

A three-generation family history includes the following:

  • First-degree relatives (e.g., children, brothers and sisters, and parents).
  • Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
  • Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
  • Additional distant relatives are included if information is available, especially when there are known cancer histories among them.

For any relative with cancer, collect the following information:

  • Primary site of each cancer, with supportive documentation of key cancers (if available) to confirm primary site and histology (e.g., pathology reports, clinical documents, and death certificates).
  • Age at diagnosis for each primary cancer.
  • Where the relative was diagnosed and/or treated.
  • History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
  • Current age (if living).
  • Age at death and cause of death (if deceased).
  • Carcinogenic exposures (e.g., tobacco use and radiation exposure).
  • Other significant health problems.

For relatives not affected with cancer, collect the following information:

  • Current age or age at death.
  • Cause of death (if deceased).
  • History of any surgeries or treatments that may have reduced the risk of cancer.
  • Cancer screening practices.
  • Any nonmalignant features associated with the syndrome in question.
  • Carcinogenic exposures.
  • Other significant health problems.

Accuracy of the family history

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives. However, people often have incomplete or inaccurate information about the cancer history in their family. A population-based survey of 2,605 first- and second-degree relatives and confirmed proband reports of cancer diagnoses found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate. Accuracy varies by cancer site and degree of relatedness. Reporting of cancer family histories may be most accurate for breast cancer and less accurate for gynecologic malignancies and colon cancer. Self-reported family histories may contain errors and, in rare instances, could be fictitious. It is important to confirm the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks, especially if decisions such as risk-reducing surgery will be based on this family history. The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.

It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family. Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years. Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.

Determining Cancer Risk

Analysis of the family history

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

  • What is the evidence that a cancer susceptibility syndrome is present in this family?
  • If a syndrome is present, what is the most probable diagnosis?
  • What could make this family history difficult to interpret?
  • What is the most likely mode of inheritance, regardless of whether a specific syndrome diagnosis can be established?
  • What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
  • If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

The following sections relate to the way that each of these questions might be addressed:

Methods of quantifying cancer risk

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions. Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented deleterious mutation has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a deleterious mutation in a cancer susceptibility gene and the risk of developing a specific form of cancer.

Risk of harboring a deleterious mutation in a cancer susceptibility gene

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a mutation. Predicting the probability of harboring a mutation in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features. All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a mutation being present in the family; others estimate the risk of a mutation being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models Web site or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and mutation probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes. In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene. In the absence of a documented mutation in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.

When a deleterious mutation has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the mutation has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability. This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the mutation identified in their family and therefore have a lower likelihood of harboring the family mutation when compared with the probability based on their relationship to the mutation carrier in the family.

Even in the case of a documented mutation on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene mutation on the other side of the family (maternal or paternal, as applicable). Segregation of more than one mutation in a family is possible (e.g., in circumstances in which a cancer syndrome has founder mutations associated with families of particular ancestral origin).

Risk of developing cancer

Unlike mutation probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a mutation in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to mutation probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented deleterious mutation, cancer risk estimates can be derived from peer-reviewed penetrance data. Penetrance data are constantly being refined and many gene mutations have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in mutation carriers include the mutation's effect on the function of the gene/protein (e.g., mutation type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA mutation). When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a gene mutation and gene mutation-specific penetrance data to calculate cancer risk.

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely. In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model). Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer. Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative. In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered. Influencing factors include the following:

  • Differential diagnosis that is consistent with the personal and cancer family history.
  • Consideration of factors that influence how informative the family history may be.
  • Population that is best suited for the use of the model.
  • Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
  • Model-specific limitations that can overestimate or underestimate calculations.

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS), but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.


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Education and Counseling About Risk/Risk Communication

Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.

The goal of genetic education and counseling is to help individuals understand their personal risk status, their options for cancer risk management, and to explore feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.

Optimally, education and counseling about cancer risk includes providing the following information:

  • Purpose, strengths, and limitations of cancer risk assessment.
  • Basic genetics and patterns of inheritance.
  • Genetic basis of cancer.
  • Clinical features of relevant hereditary cancer syndromes.
  • Evidence of a hereditary cancer syndrome from the consultand's personal and family history.
  • Options for clarifying cancer risk, including genetic testing, if indicated.
  • Options available for risk management, including data (or lack of data) on the efficacy of different measures for early detection and risk reduction.
  • Signs and symptoms of cancer.

When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:

  • Risk of having a mutation and patterns of transmission.
  • Alternatives to genetic testing.
  • Risks, benefits and limitations of genetic testing, including psychological and discriminatory risks.
  • Possible test outcomes, including likelihood of uninformative results and identifying variants of uncertain significance.
  • Sensitivity of the genetic test, including the techniques utilized to perform the test and their associated limitations.
  • Health care management options based on possible test results.
  • Implications for children and other family members based on pattern of transmission.
  • Dissemination of risk and genetic information to family members.
  • Cost associated with testing, counseling, medical management, and options for insurance coverage.
  • How genetic information and genetic test results will be recorded in the medical record.
  • Specimen storage and reuse, if applicable.

If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:

  • Interpretation of test results.
  • Discussion of further testing that may clarify risk (e.g., large rearrangement testing and testing the other genes based on the patient's differential cancer syndrome list).
  • Assessment of the emotional and behavioral responses to genetic test results.
  • Recommendations for coping and communication strategies to address issues related to cancer risk.
  • Cancer risk management recommendations.
  • Risk analysis and dissemination of risk results to family members.

The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.

Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.

Methods of Risk Presentation

The usage of numerical probabilities to communicate risk may overestimate the level of risk certainty, especially when wide confidence intervals exist to the estimates or when the individual may differ in important ways from the sample on which the risk estimate was derived. Also, numbers are often inadequate for expressing gut-level or emotional aspects of risk. Finally, there are wide variations in individuals’ level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided. Additionally, important “contextual” risks may be included with the frequency in order to increase risk comprehension; these may include how the person’s risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.

The communication of risk may be numerical, verbal, or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information. Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful in avoiding problems with comprehension of numbers, but research that confirms this is lacking. A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Results indicate that overall, there were no differences in improved accuracy of risk perception between the two groups, but among those women who inaccurately perceived very high risk at baseline, the group receiving both visual aids showed greater improvement in accuracy.

Risk Communication

The purpose of risk counseling is to provide individuals with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. A systematic review of 28 studies that evaluated communication interventions showed that risk communication benefits users cognitively by increasing their knowledge and understanding of risk perception and does not negatively influence affect (anxiety, cancer-related worry, and depression). Risk communication does not appear to result in a change in use of screening practices and tests. Users received the most benefit from an approach utilizing risk communication along with genetic counseling. Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity, and other psychological processes on the part of individuals and providers. Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having an adverse event; in relative or absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individual’s perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") or risk information presented as a ratio (e.g., 1 in 4). A strong preference for having BRCA1/2 mutation risk estimates expressed numerically is reported by women considering testing. Individuals associate widely differing quantitative risks with qualitative descriptors of risk such as “rare” or “common.” More research is needed on the best methods of communicating risk in order to help individuals develop an accurate understanding of their cancer risks.

Communication Strategies

Recent descriptive examination of the process of cancer genetic counseling has found that counseling sessions are predominantly focused on the biomedical teaching required to inform clients of their choices and to put genetic findings in perspective but that attention to psychosocial issues does not detract from teaching goals and may enhance satisfaction in clients undergoing counseling. For instance, one study of communication patterns in 167 pretest counseling sessions for BRCA1 found the sessions to have a predominantly biomedical and educational focus; however, this approach was client focused, with the counselor and client contributing equally to the dialogue. These authors note that there was a marked diversity in counselor styles, both between counselors and within different sessions, for each counselor. The finding of a didactic style was corroborated by other researchers who examined observer-rated content checklists and videotape of 51 counseling sessions for breast cancer susceptibility. Of note, genetic counselors seemed to rely on demographic information and breast cancer history to tailor genetic counseling sessions rather than client’s self-reported expectations or psychosocial factors. Concurrent provision of psychosocial and scientific information may be important in reducing worry in the context of counseling about cancer genetics topics. An increasing appreciation of language choices may contribute to enhanced understanding and reduced anxiety levels in the session; for example, it was noted that patients may appreciate synonymic choices for the word “mutation,” such as “altered gene”. Some authors have published recommendations for cultural tailoring of educational materials for the African-American population, such as a large flip chart, including the use of simple language and pictures, culturally identifiable images (e.g., spiritual symbols and tribal patterns), bright colors, and humor.

Literature that examines novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer is being developed. Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the client’s personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for BRCA1/2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated. Other modalities include the development of checklists, CD-ROM programs, and interactive computer programs. Checklists have been developed to ensure coverage of important topics in the counseling session and include those completed by observers or by the patients themselves to clarify their goals and needs in the counseling session. One study compared a feedback checklist completed by 197 women attending a high-risk breast clinic prior to the counseling session to convey prior genetic knowledge and misconceptions to aid the counselor in tailoring the session for that client. The use of the feedback checklist led to gains in knowledge from the counseling session but did not reduce genetic counseling time, perhaps because the genetic counselor chose to spend time discussing topics such as psychosocial issues. Use of the checklist did decrease the time spent with the medical oncologist, however. The feedback checklist was compared to a CD-ROM that outlined basic genetic concepts and the benefits and limitations of testing and found that those viewing the CD-ROM spent less time with counselors and were less likely to choose to undergo genetic testing. The CD-ROM did not lead to increased knowledge of genetic concepts, as did use of the checklist.

A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria. The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, decisional conflict decreased because participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.

Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed. The authors evaluated the influence of the communication aid in 27 women at high risk of a BRCA1/2 mutation and compared those who had read the aid to a comparison sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid, with no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling. In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for BRCA1/2 testing. Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a BRCA1/2 mutation. Many of the counselors reported that their client’s use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients’ unique concerns.

Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels. Similarly, teleconferencing sessions, in which the client and genetic specialists were able to talk with each other in real time, were used in rural Maine communities in the pediatric context to convey genetic information and findings for developmental delays and were found to be comparable to in-person consultations in terms of decision-making confidence and satisfaction with the consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.


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The Option of Genetic Testing

Factors to Take into Consideration in Offering Testing

Indications for testing

Experts recommend offering genetic testing when a risk assessmentsuggests the presence of an inherited cancer syndrome for which specific genes have been identified. The American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility proposes that genetic testing be offered when the following conditions apply:

  • An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
  • The results of the test can be interpreted.
  • Testing will influence medical management.

Characteristics used in making this determination are discussed in the PDQ summaries on the genetics of specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks, benefits, and limitations, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.

In 2010, ASCO updated its policy statement to address testing for low- to moderate-penetrance genes, multiplex genomic tests, and direct-to-consumer (DTC) testing. This current ASCO framework (Table 1) recommends that the provider consider the evidence for clinical utility of the test in addition to whether the test was obtained through a health care provider or directly by the consumer.

ASCO’s position is that when a test, regardless of clinical utility, is ordered by a health care professional, the provider is responsible for organizing follow-up care based on the findings. For tests that were ordered by the consumer without health care professional involvement, management decisions are based on the evidence for clinical utility. For tests with accepted clinical utility, follow-up care can be guided by the evidence for cancer risk associated with the genetic test finding. However, in tests ordered by the consumer that have uncertain clinical utility, ASCO recommends that follow-up care consist of education regarding the lack of evidence regarding the test's clinical utility and that cancer risk management decisions be guided by established cancer risk factors.

Genetic education and counseling, including the interpretation of genetic test results, will vary depending on whether a previous attempt at genetic testing has been made (see Figure 2). In general, there are two primary circumstances in which genetic testing is performed:

  • Families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a mutation.
  • Families with a documented deleterious mutation.

Value of testing an affected family member first

Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. Three possible outcomes for this form of testing include the following (see Figure 2):

If a mutation that is documented to be deleterious (associated with cancer risk) is identified, risks are based on penetrance data for mutations of that specific gene. In addition, other family members may be tested for the presence or absence of this specific mutation. If no mutation is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a mutation in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:

  • The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
  • The cancer in the family may be associated with a gene mutation, but the cancer in the specific family member who underwent testing is not associated with that mutation. This can occur especially with cancers that are common in the general population, such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the mutated gene associated with the inherited predisposition to cancer in the family is considered a phenocopy.
  • Identifying a gene mutation may not be possible given the limited sensitivity of the laboratory techniques used to detect mutations. There may be additional testing available to detect certain types of mutations that would have been missed by the initial genetic test.
  • The function of the gene could be altered by a mutation in a different gene.

Lastly, testing may reveal a variant of uncertain significance. This result means that a gene mutation has been found; however, the extent that this mutation increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the mutation can be derived from the following:

  • The location of the mutation in relation to regions and function of a gene.
  • The specific change; since many variants are missense mutations, not all amino acid substitutions are as significant.
  • Whether the variant has been documented in the presence of a documented deleterious mutation.
  • Whether the mutation is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.

Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.

If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. These generally involve weighing the availability and reliability of testing the stored tissue of a deceased relative or testing an unaffected person without prior testing of an affected family member. Tests done on stored tissue are technically difficult and may not yield a definitive result. Testing an unaffected person without prior testing of an affected relative often is uninformative because a negative test does not rule out the presence of a cancer susceptibility gene in the family or the subject.

Testing in families with a documented deleterious mutation

Genetic susceptibility testing for a documented deleterious mutation in the family can be very informative and will yield one of the following two results (see Figure 2):

  • Positive for the familial mutation.
  • Negative for the familial mutation.

If the familial mutation is detected in a family member, their cancer risks are based on penetrance data for mutations in that specific gene. If the documented mutation is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented mutation may increase the cancer risk above the general population levels.

In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test, all possible test outcomes, and the consequences of identifying a variant of unknown clinical significance.

Genetic testing and assisted reproductive technology

Advances in reproductive technology have enabled predisposition cancer genetic testing to be performed in the prenatal setting using chorionic villus sampling and amniocentesis and in the preimplantation setting using preimplantation genetic diagnosis. A literature review coupled with a brief survey found 55 case reports of prenatal or preimplantation diagnosis performed for cancer predisposition for more than 12 familial cancer syndromes. In a telephone survey of 13 centers listed in an online resource as providing preimplantation genetic diagnosis, nine reported they provided this service for cancer predisposition syndromes.

Reproductive medicine used in the context of predisposition genetic testing for cancer risk raises important ethical, legal, and social issues. A proposed analytic framework recommends considering the following issues:

When counseling cancer susceptibility gene mutation carriers who are considering childbearing, it is important to address the issues listed above while maintaining sensitivity to the potential parents' personal beliefs.

Determining the Test to be Used

Genetic testing is highly specialized. A given test is usually performed in only a small number of laboratories. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colon cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be caused by mutations in one of several mismatch repair [MMR] genes).

In some genes, the same mutation has been found in multiple, apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. Other genes also have reported founder mutations. The presence of founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, approximately 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations. Also, for genes in which large genome rearrangements are founder mutations, ordering additional testing using different techniques may be needed.

Allelic heterogeneity (i.e., different mutations within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) gene mutations are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC mutations cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk. In addition, other disorders may be part of the FAP spectrum. Mutations in a certain portion of the APC gene also predispose to retinal changes, for example, when mutations in a different region of APC predispose to desmoid tumors. Thus, selection of the appropriate genetic test for a given individual requires considerable knowledge of genetic diagnostic methods, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)

Regulation of genetic tests

Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination. The Centers for Medicare & Medicaid Services, using the Clinical Laboratory Improvement Act (CLIA), regulates all clinical human laboratory testing performed in the United States for the purposes of generating diagnostic or other health information. CLIA regulations address personnel qualifications, laboratory quality assurance standards, and documentation and validation of tests and procedures. For laboratory tests themselves, CLIA categorizes tests based on the level of complexity into waived tests, moderate complexity, or high complexity. Genetic tests are considered high complexity, which indicates that a high degree of knowledge and skill is required to perform or interpret the test. Laboratories conducting high complexity tests must undergo proficiency testing at specified intervals, which consists of an external review of the laboratory's ability to accurately perform and interpret the test. However, a specialty area specific for molecular and biologic genetic tests has yet to be established; therefore, specific proficiency testing of genetic testing laboratories is not required by CLIA.

In regard to analytic validity, genetic tests fall into two primary categories; test kits and laboratory-developed tests (previously called home brews). Test kits are manufactured for use in laboratories performing the test and include all the reagents necessary to complete the analysis, instructions, performance outcomes, and details about which mutations can be detected. The U.S. Food and Drug Administration (FDA) regulates test kits as medical devices; however, despite more than 1,000 available genetic tests, there are fewer than ten FDA-approved test kits. Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house; this category represents the most common form of genetic testing. Laboratory-developed tests are subject to the least amount of oversight, as neither CLIA nor the FDA evaluate the laboratories' proficiency in performing the test or clinical validity relative to the accuracy of the test to predict a clinical outcome. The FDA does regulate manufactured analyte-specific reagents (ASRs) as medical devices. These small molecules are used to conduct laboratory-developed tests but can also be made by the laboratory. ASRs made in the laboratory are not subject to FDA oversight. For laboratory-developed tests utilizing manufactured commercially available ASRs, the FDA requires that the test be ordered by a health professional or other individual authorized to order the test by state law. However, this regulation does not distinguish between health providers caring for the patient or health providers who work for the laboratory offering the test.

In addition to classical clinical genetic tests is the regulatory oversight of research genetic testing. Laboratories performing genetic testing on a research basis are exempt from CLIA oversight if the laboratory does not report patient-specific results for the diagnosis, prevention, or treatment of any disease or impairment or the assessment of the health of individual patients. However, there are anecdotal reports of research laboratories providing test results for clinical purposes with the caveat that the laboratory recommends that testing be repeated in a clinical CLIA-approved laboratory. In addition, there is no established mechanism that determines when a test has sufficient analytic and clinical validity to be offered clinically. Currently, the decision to offer a genetic test clinically is at the discretion of the laboratory director.

Evidence regarding the implications of this narrow regulatory oversight of genetic tests is limited and consists predominately of laboratory director responses to quality assurance surveys. A survey of 133 laboratory directors performing genetic tests found that 88% of laboratories employed one or more American Board of Medical Genetics (ABMG)-certified or ABMG-eligible professional geneticists, and 23% had an affiliation with at least one doctoral-prepared geneticist. Eight percent of laboratories did not employ and were not affiliated with doctoral-level genetics professionals. Laboratory-developed tests were performed in 70% of laboratories. Sixty-three percent of laboratories provided an interpretation of the test result as part of the test report. Another survey of 190 laboratory directors found that 97% were CLIA-certified for high complexity testing. Sixteen percent of laboratories reported no specialty area certification; those without specialty certification represented laboratories with the most volume of tests performed and offered the most extensive test selection. Of laboratories with specialty certification, not all had certification relevant to genetic tests, with 48% reporting pathology certification, 46% chemistry certification, and 41% clinical cytogenetics certification. Sixteen percent of directors reported participation in no formal external proficiency testing program, although 77% performed some informal proficiency testing when a formal external proficiency testing program was not available.

The most frequent reason cited for lack of proficiency testing participation was lack of available proficiency testing programs. Laboratory directors estimated that in the past 2 years 37% issued three or fewer incorrect reports, and 35% issued at least four incorrect reports. Analytic errors such as faulty reagent, equipment failure, or human error, increased 40% with each decrease in level of proficiency training completed. An international genetic testing laboratory director survey involving 18 countries found that 64% of the 827 laboratories that responded accepted samples from outside their country. Similar to the U.S. study, 74% reported participation in some form of proficiency testing. Fifty-three percent of the laboratories required a copy of the consent to perform the test, and 72% of laboratories retained specimens indefinitely that were submitted for testing.

The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Genetics, Health, and Society has published a detailed report regarding the adequacy and transparency of the current oversight system for genetic testing in the United States. The Committee identified gaps in the following areas:

  • Regulations governing clinical laboratory quality.
  • Oversight of the clinical validity of genetic tests.
  • The number and identification of laboratories performing genetic tests and the specific genetic tests being performed.
  • Level of current knowledge about the clinical usefulness of genetic tests.
  • Educational preparation in genetics of health providers, the public health community, patients, and consumers.

Direct-to-Consumer (DTC) Marketing of Genetic Tests

Over the last decade there has been a marked increase in companies advertising or providing genetic services directly to the consumer. Accordingly, it is inevitable that an increasing number of patients will approach physicians and genetic counselors armed with information or genetic test results from DTC companies. In the next sections, information is provided about: (1) trends in DTC marketing of genetic tests; (2) concerns about DTC marketing of genetic tests; and (3) research examining the impact of DTC marketing of genetic tests.

Trends in DTC marketing of genetic tests

In 2002, a search of Internet-based studies found 14 genetic testing companies advertising adult health-related susceptibility testing, with only three companies actually offering testing directly to the public. A 2005 and 2006 study identified 24 Internet-based companies providing DTC testing. The companies surveyed offered diverse types of testing, including diagnostic tests for single high-penetrance diseases, such as Huntington disease; risk assessment tests for polygenic diseases, such as breast cancer and Alzheimer disease; and testing for many low penetrance genes that may have ramifications for health or well being, such as nutrigenomic or nutrigenetic tests or cardiovascular profiles. About one-quarter (24%) offered diagnostic and risk assessment tests; 21% offered all genetic tests; 21% offered enhancement tests only; 17% offered risk assessment and enhancement tests; 13% offered diagnostic tests only; and one company (4%) offered risk assessment tests only. The investigators for this study defined enhancement test as a test for one or more low-penetrance genes for the purpose of providing information on general aspects of health, nutrition, and/or treatment regimens, such as nutrigenetic or pharmacogenetic tests and cardiovascular health profiles. This study also examined the content of the Internet information and found that companies offering diagnostic and risk assessment tests were much more likely to indicate that a physician associated with the company would be involved in interpreting the tests than companies offering enhancement testing. Of these companies, eight did not require a physician to be involved in ordering tests or interpreting the results. More than 75% of the 24 companies stated that they recommended or provided phone-based genetic counseling services. When genetic counseling was offered by the company, there was no information provided about the qualifications of the counselors and the scope of the information and counseling provided.

DTC genetic testing in children

One study identified 48 DTC companies and was able to contact 37 of them between December 2009 and April 2010 regarding participation in a survey about their company policies for testing children. Thirteen of the 37 companies participated in the survey, despite guarantees of confidentiality. Ten of 13 (77%) companies reported that they allowed genetic testing of minors; of these ten, nine reported receiving requests to test minors from parents or legal guardians. One company reported receiving a direct request from a minor to be tested. The investigators did not collect data on the types of tests the DTC companies provide; however, the implication is that most of the tests offered evaluate genetic susceptibility to adult-onset disorders.

Concerns about marketing of DTC genetic tests

Several professional organizations have released position statements or recommendations cautioning against DTC advertising and provision of genetic tests. The main concerns that are expressed within these statements include the following:

In 2004, The American College of Medical Genetics Board of Directors asserted that genetic testing for susceptibility to disease are medical tests; therefore, these tests should be provided to the public through qualified health care professionals only. Given the complexities of genetic testing and counseling, telephone or Internet orders of home testing kits may be harmful because of the potential for inappropriate test use, misinterpretation of results, and lack of follow-up. More recently, the American Society of Human Genetics (ASHG) provided a policy statement on DTC genetic testing, citing the need for broader oversight of laboratory assessments by the FDA and Federal Trade Commission (FTC) in order to ensure reliable tests. The ASHG statement recommended a series of standards in the area of transparency, provider education, and test and laboratory quality, and concluded that further research and federal oversight are needed in this rapidly changing field. In 2006, the FTC and Centers for Disease Control and Prevention issued a joint statement to consumers regarding the limitations of DTC genetic tests.

Proponents of DTC marketing and provision of genetic tests often assert the putative "right to information," which they argue promotes patient autonomy. DTC marketing may increase patients’ feelings of empowerment to discuss their care with their physicians. Patients may also develop an increased awareness of the importance of family history, the relationship between risk and family history, the role of genetics in disease, and a better understanding of the value of genetic counseling. While the issue of privacy is also emphasized in DTC marketing and testing claims, it may not be as salient after testing, given that those found to be positive will, for the most part, want their physician involved early in identifying measures to mitigate risk.

Research examining the impact of DTC marketing of genetic tests

Marketing of DTC genetic tests includes diverse strategies for increasing awareness and market demand for genetic testing services by for-profit companies. There are two approaches to targeting consumers with information about DTC genetic tests. The first is called DTC advertising, which promotes the availability of a genetic test to the public but requires involvement of a health care provider to order the test and disseminate the results to the consumer. The second approach, DTC genetic testing, is discussed below. While numerous position papers, review articles, and commentaries have been published, there are few empirical examples about the impact of DTC advertising of genetic tests on patients, providers, or the health care system. The most studied example to date is the Myriad Genetics campaign to increase awareness of BRCA1/2 mutation testing through multiple mass media outlets (print, radio, and television). In 2002, Myriad launched its first DTC marketing campaign in Denver and Atlanta. The target audience for this campaign was women from the general population aged 25 to 54 years. In May 2002, Myriad began with educational outreach to providers in the two cities in anticipation of patient requests for information spurred by the DTC campaign, which ran from September 2002 to February 2003. The campaign included television, radio, and print advertisements that were expected to reach greater than 90% of the target audience an average of 16 times during the 5-month period. Subsequently, these DTC campaigns have been conducted in the northeast, Texas, and Florida. These campaigns were immediately criticized for providing incomplete, manipulative information.

Empirical research was conducted immediately following the 2002 campaign. A random digit dialing survey of 1,635 women in the campaign cities (Denver and Atlanta) and two control cities found increased levels of awareness of BRCA1/2 genetic testing in target cities. However, no significant differences were observed in perceived knowledge about testing, concern about breast cancer, or interest in testing. There was no evidence that knowledge was differentially increased in those women with strong family histories of breast cancer, who would most benefit from consideration of testing. No overall increase in anxiety or confusion about testing was reported. Of women who reported exposure to the DTC advertisement, 63% reported no anxiety at all, and 76% reported no confusion. A smaller study of 315 women from the Denver area found that women at increased risk of breast cancer were more knowledgeable about BRCA testing and more likely to recall the advertisement. However, an equal number of high and low risk women felt they would benefit from genetic testing and were interested in testing. A consumer survey based on a cross-sectional, stratified, random sample of at-risk women explored the effects of socioeconomic status (SES) on women’s reactions to a BRCA1/BRCA2 genetic testing DTC marketing campaign. The survey was conducted at two intervention sites (n = 811) and two control sites (n = 824), and knowledge of the genetic test, perceptions of personal risk, communications with others about the test, and interest in pursuing the test were evaluated. SES, as measured by income and education, had no differential effect on any of the outcome measures in women at the intervention sites and control sites. However, the study did report a consistent overall effect of SES on most variables measured, independent of the intervention site. For example, women of lower SES reported being less knowledgeable about genetics and risk, yet were more interested in genetic testing. These results suggest that SES could play a role in access to genetic services, how women understand their genetic risk of inherited breast and ovarian cancer susceptibility, and what they do about it.

The impact of the advertising campaign on physicians was also a focus of investigation. Physicians in target cities were more likely to remember hearing an advertisement for testing but did not have increased knowledge compared with physicians in control cities. Physicians in target cities reported increases in patients’ questions about genetic testing, genetic counseling referrals, and requests for testing. In summary, physicians might have been more likely to make a referral for testing based on the patient’s interest in testing, whether or not the doctor is informed enough to consider whether the test is appropriate. The most concerning documented problem with this campaign was that the company targeted the general population, even though genetic testing for BRCA1/2 is only appropriate for a subgroup of women.

In addition to the data from the Myriad campaign, one international study examined the impact of a DTC campaign for genetic testing by a group of researchers in partnership with a popular Polish women’s magazine (Twoj Styl). Genetic testing was offered to 5,000 women through an announcement placed in Twoj Styl in October 2001. A total of 5,024 women who qualified received a free genetic test for three BRCA1 mutations that are common in Poland. Genetic counseling was offered only to women with a positive test or with a significant family history of breast or ovarian cancer. The great majority of women who took part in the program expressed a high degree of satisfaction, and after 1 year, approximately two-thirds of identified mutation carriers had complied with breast cancer screening recommendations. No follow-up with women who received a negative test result to assess understanding of their results was conducted nor was subsequent follow-up conducted regarding population screening recommendations.

Research examining DTC testing

DTC genetic testing is advertised directly to consumers, purchased directly by the consumer, and the results are delivered directly to the consumer without the involvement of the consumer’s health care provider. Some might suggest that DTC genetic tests promise heightened privacy and the potential that individuals will be more informed and more able to take an active, decision-making role in their medical options.

DTC laboratories predominantly rely on Web material to disseminate test information to consumers. One study evaluated how using a Web-based decision tool that provided information about a multiplex genetic susceptibility test influenced participants’ testing decisions. The Web-based tool was developed specifically for the study by an interdisciplinary research team and was designed using principles of health literacy, communication, and prior research. The tool implemented a layered menu approach that allowed participants to select the order and amount of content viewed. Participants included 526 members of a large Midwestern health maintenance organization ranging in age from 25 to 40 years with no evidence of any of the health conditions included in the test. Participants most frequently viewed the Web pages describing the test, testing procedures, and implications of the results and less frequently viewed the pages about specific health conditions or genes. Participants viewed an average of eight Web pages (mean 8.2, standard deviation 7.2, range 1–27), including an average of 2.9 of the 4 pages introducing the multiplex test, 2.2 of the 8 pages describing the health conditions on the test, and 3.2 of the 15 pages describing the genes, out of a possible 27 total pages. The number of Web pages viewed was significantly associated with ease of decision making (odds ratio, 1.04; 95% CI, 1.01–1.07).

There is growing interest in trying to use genetic information to guide decisions about healthy lifestyle, including dietary choice, although there is no evidence base for implementing such practices. A 2006 study of consumer and physician awareness of DTC nutrigenomic tests found that 14% of consumers and 44% of physicians had heard of the tests, but actual utilization was exceedingly low (0.6% of consumers had used one). This study examines awareness of nutrigenomic testing in Michigan, Oregon, and Utah via the 2006 Behavioral Risk Factors Surveillance System. Awareness was highest in Oregon (24.4%) and Utah (19.7%) and lowest in Michigan (7.6%). Those who had higher incomes, greater education, and increasing age (except those older than 65 years) were more aware of nutrigenomic tests. Of those consumers who had heard of DTC nutrigenomic tests, 46% had heard about them from television, 35% from magazines, 29% from newspapers, and only 13% from health professionals. There was great variation in the extent to which background information concerning the disease in question was presented. For example, more than half of these companies offered information about disease etiology, but far fewer offered information about diagnosis and treatment or prevention. Companies providing tests of little clinical utility (such as enhancement tests) tended to provide more detailed information, although the information provided about the diseases and genetics in general was not always accurate, as clinical validity claims were supported by peer-reviewed literature in only approximately half the companies. The trend identified in this survey of available companies indicates that the tests with the least clinical utility are provided with the least professional oversight and counseling services.

A study of 1,087 users of Facebook, a social-networking Web site, who proactively registered with a marketing firm indicated that almost half of respondents were aware of personal genetic testing (PGT). Fewer than 10% of respondents had used PGT for a variety of conditions, including, but not limited to, cancer; however, the majority indicated that they would consider using PGT (64%). The study also identified key areas in which individuals may benefit from additional education and information. For example, one-third of respondents mistakenly understood that the PGT results indicated a diagnosis of disease as opposed to risk of developing disease. In addition, respondents viewed physicians as an important resource in understanding and using PGT results to make health care decisions.

Another study examined how 145 Facebook users interpreted DTC information. Participants completed an online survey in which separate scenarios containing information derived from DTC Web sites about the risk of developing heart disease, colorectal cancer, or basal cell skin cancer were presented. The authors found that even in this highly educated cohort, of whom 56% were in the health care field, the reported ease of understanding the test results was not related to an accurate interpretation of the results. Of those who answered that the results were easy or very easy to understand for each of the scenarios, correct interpretation varied greatly (59%–80%) across the four scenarios.

A study offered DTC genomic risk assessments at reduced cost to 3,640 highly educated (90% had some college or more), high-income (median, $100,000–$149,000 per year), predominantly white (80%) employees in the health care (the sponsoring institution), technology, and biotechnology fields. Those who declined participation were more likely to be nonwhite. Among those who underwent DTC testing, about half (49.7%) expressed testing-related concerns; the most frequently cited concerns involved privacy issues. In multivariate analyses, female gender, employment in a health care field, younger age, higher education, and higher trait anxiety were significant predictors of expressing concerns about testing. The majority (82.4%) indicated that they would want to know their genetic risk of a nonpreventable disease. Women, whites, those who were younger, those who were in health-related occupations, and those who had higher trait anxiety expressed more uncertainty about whether they would want to know their genetic risk of a nonpreventable disease.

Of the 56% of participants who provided a 3-month follow-up assessment, there was neither evidence of clinically meaningful distress and health behavior change (dietary fat intake, exercise) nor a statistically significant difference in screening test uptake compared with baseline measures. Illness-specific worry was not assessed. Only 10% of participants had discussed their test results with a DTC company-specific genetic counselor; only 27% had discussed their results with their physician.

Informed Consent

Informed consent can enhance preparedness for testing, including careful weighing of benefits and limitations of testing, minimization of adverse psychosocial outcomes, appropriate use of medical options, and a strengthened provider-patient relationship based on honesty, support, and trust.

Consensus exists among experts that a process of informed consent should be an integral part of the pretest counseling process. This view is driven by several ethical dilemmas that can arise in genetic susceptibility testings. The most commonly cited concern is the possibility of insurance or employment discrimination if a test result, or even the fact that an individual has sought or is seeking testing, is disclosed. In 2008, Congress passed the Genetic Information Nondiscrimination Act (GINA). This federal law provides protections related to health insurance and employment discrimination based on genetic information. However, GINA does not cover life, disability, or long-term-care insurance discrimination. A related issue involves stigmatization that may occur when an individual who may never develop the condition in question, or may not do so for decades, receives genetic information and is labeled or labels himself or herself as ill. Finally, in the case of genetic testing, medical information given to one individual has immediate implications for biologic relatives. These implications include not only the medical risks but also disruptions in familial relationships. The possibility for coercion exists when one family member wants to be tested but, to do so optimally, must first obtain genetic material or information from other family members.

Inclusion of an informed consent process in counseling can facilitate patient autonomy. It may also reduce the potential for misunderstanding between patient and provider. Many clinical programs provide opportunities for individuals to review their informed consent during the genetic testing and counseling process. Initial informed consent provides a verbal and/or written overview of the process.

Some programs use a second informed consent process prior to disclosure to the individual of his or her genetic test results. This process allows for the possibility that a person may change his or her mind about receiving test results. After the test result has been disclosed, a third informed consent discussion often occurs. This discussion concerns issues regarding sharing the genetic test result with health providers and/or interested family members, currently or in the future. Obtaining written permission to provide the test result to others in the family who are at risk can avoid vexing problems in the future should the individual not be available to release his or her results.

Core elements of informed consent

Major elements of an informed consent discussion are highlighted in the preceding discussion. The critical elements, as described in the literature, include the following:

  • Elicitation and discussion of a person’s expectations, beliefs, goals, and motivations.
  • Explanation of how inheritance of genetic factors may affect cancer susceptibility.
  • Clarification of a person’s increased risk status.
  • Discussion of potential benefits, risks, and limitations of testing.
  • Discussion of costs and logistics of testing and follow-up.
  • Discussion of possible outcomes of testing (e.g., true positive, true negative, variant of uncertain significance, inconclusive, false positive).
  • Discussion of medical management options based on risk assessment and/or test results available for those who choose to test; for those who choose not to test, and for those who have positive, negative, or inconclusive results).
  • Data on efficacy of methods of cancer prevention and early detection.
  • Discussion of possible psychological, social, economic, and family dynamic ramifications of testing or not testing.
  • Discussion of alternatives to genetic testing (e.g., tissue banking, risk assessment without genetic testing).
  • Attainment of verbal and written informed consent or clarification of the decision to decline testing.

All individuals considering genetic testing should be informed that they have several options even after the genetic testing has been completed. They may decide to receive the results at the posttest meeting, delay result notification, or less commonly, not receive the results of testing. They should be informed that their interest in receiving results will be addressed at the beginning of the posttest meeting (see below) and that time will be available to review their concerns and thoughts on notification. It is important that individuals receive this information during the pretest counseling to ensure added comfort with the decision to decline or defer result notification even when testing results become available.

Testing in children

Genetic testing for mutations in cancer susceptibility genes in children is particularly complex. While both parents and providers may request or recommend testing for minor children, many experts recommend that unless there is evidence that the test result will influence the medical management of the child or adolescent, genetic testing should be deferred until legal adulthood (age 18 years or older) because of concerns about autonomy, potential discrimination, and possible psychosocial effects. A number of cancer syndromes include childhood disease risk, such as retinoblastoma, multiple endocrine neoplasia (MEN) types 1 and 2 (MEN1 and MEN2), neurofibromatosis types 1 and 2 (NF1 and NF2), Beckwith–Wiedemann syndrome, Fanconi anemia, FAP, and Von Hippel-Lindau disease (VHL). As a consequence, decisions about genetic testing in children are made in the context of a specific gene in which a mutation is suspected. The ASCO statement on genetic testing for cancer susceptibility maintains that the decision to consider offering childhood genetic testing should take into account not only the risk of childhood malignancy but also the evidence associated with risk reduction interventions for that disorder. Specifically, ASCO recommends that:

  • When screening or preventive strategies during childhood are available (e.g., MEN and FAP), testing should be encouraged on clinical grounds.
  • When no risk reduction strategies are available in childhood and the probability of developing a malignancy during childhood is very low (e.g., hereditary breast/ovarian cancer syndrome), testing should not be offered.
  • Some patients may be at risk of developing a malignancy during childhood without the availability of validated risk-reduction strategies (e.g., TP53 mutations). The decision to test in such circumstances is particularly controversial.

Special considerations are required when genetic counseling and testing for mutations in cancer susceptibility genes are considered in children. The first issue is the age of the child. Young children, especially those younger than 10 years, may not be involved or may have limited involvement in the decision to be tested, and some may not participate in the genetic counseling process. In these cases, the child’s parents or other legal surrogate will be involved in the genetic counseling and will ultimately be responsible for making the decision to proceed with testing. Counseling under these circumstances incorporates a discussion of how test results will be shared with the child when he or she is older. Children aged 10 to 17 years may have more involvement in the decision-making process. In a qualitative study of parents and children aged 10 to 17 years assessing decision making for genetic research participation, older, more mature children and families with open communication styles were more likely to have joint decision making. The majority of children in this study felt that they should have the right to make the final decision for genetic research participation, although many would seek input from their parents. While this study is specific to genetic research participation, the findings allude to the importance children aged 10 to 17 years place on personal decision making regarding factors that impact them. Unfortunately cognitive and psychosocial development may not consistently correlate with the age of the child. Therefore, careful assessment of the child’s developmental stage may help in the genetic counseling and testing process to facilitate parent and child adaptation to the test results. Another complicating factor includes potential risks for discrimination. (Refer to the Employment and Insurance Discrimination section in the Ethical, Legal, and Social Implications section of this summary for more information.)

The consequences of genetic testing in children have been reviewed. In contrast to observations in adults, young children in particular are vulnerable to changes in parent and child bonding based on test results. Genetic testing could interfere with the development of self-concept and self-esteem. Children may also be at risk of developing feelings of survivor guilt or heightened anxiety. All children are especially susceptible to not understanding the testing, results, or implications for their health. As children mature, they begin to have decreased dependency on their parents while developing their personal identity. This can be altered in the setting of a serious health condition or an inherited disorder. Older children are beginning to mature physically and develop intimate relationships while also changing their idealized view of their parents. All of this can be influenced by the results of a genetic test. In its recommendations for genetic testing in asymptomatic minors, the European Society of Human Genetics emphasizes that parents have a responsibility to inform their children about their genetic risk and to communicate this information in a way that is tailored to the child’s age and developmental level.

In summary, the decision to proceed with testing in children is based on the use of the test for medical decision making for the child, the ability to interpret the test, and evidence that changes in medical decision making in childhood can positively impact health outcomes. Deferral of genetic testing is suggested when the risk of childhood malignancy is low or absent and/or there is no evidence that interventions can reduce risk. When offering genetic testing in childhood, consideration of the child’s developmental stage is used to help determine his or her involvement in the testing decision and who has legal authority to provide consent. In addition, careful attention to intrafamilial issues and potential psychosocial consequences of testing in children can enable the provider to deliver support that facilitates adaptation to the test result. (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about psychosocial research in children being tested for specific cancer susceptibility gene mutations.)

Testing in vulnerable populations

Genetic counseling and testing requires special considerations when used in vulnerable populations. In 1995, the American Society of Human Genetics published a position statement on the ethical, legal, and psychosocial implications of genetic testing in children and adolescents as a vulnerable population. However, vulnerable populations encompass more than just children. Federal policy applicable to research involving human subjects, 45 CFR Code of Federal Regulations part 46 Protection Of Human Subjects, considers the following groups as potentially vulnerable populations: prisoners, traumatized and comatose patients, terminally ill patients, elderly/aged persons who are cognitively impaired and/or institutionalized, minorities, students, employees, and individuals from outside the United States. Specific to genetic testing, the International Society of Nurses in Genetics further expanded the definition of vulnerable populations to also include individuals with hearing and language deficits or conditions limiting communication (for example, language differences and concerns with reliable translation), cognitive impairment, psychiatric disturbances, clients undergoing stress due to a family situation, those without financial resources, clients with acute or chronic illness and in end-of-life, and those in whom medication may impair reasoning.

Genetic counseling and testing in vulnerable populations raises special considerations. The aim of genetic counseling is to help people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, which in part involves the meaningful exchange of factual information. In a vulnerable population, health care providers need to be sensitive to factors that can impact the ability of the individual to comprehend the information. In particular, in circumstances of cognitive impairment or intellectual disability, special attention is paid to whether the individual’s legally authorized representative should be involved in the counseling, informed consent, and testing process.

Providers need to assess all patients for their ability to make an uncoerced, autonomous, informed decision prior to proceeding with genetic testing. Populations that do not seem vulnerable (e.g., legally adult college students) may actually be deemed vulnerable because of undue coercion for testing by their parents or the threat of withholding financial support by their parents based on a testing decision inconsistent with the parent’s wishes. Alteration of the genetic counseling and testing process may be necessary depending on the situation, such as counseling and testing in terminally ill individuals who opt for testing for the benefit of their children, but given their impending death, results may have no impact on their own health care or may not be available before their death. In summary, genetic counseling and testing requires that the health care provider assess all individuals for any evidence of vulnerability, and if present, be sensitive to those issues, modify genetic counseling based on the specific circumstances, and avoid causing additional harm.

Importance of Pretest Counseling

The complexity of genetic testing for cancer susceptibility has led experts to suggest that careful, in-depth counseling should precede any decision about the use of testing, in keeping with the accepted principles for the use of genetic testing. For example, New York State guidelines specify that “When an increased risk for hereditary susceptibility is identified through the individual or family history, the clinician should initiate discussion or refer the patient for information concerning genetic testing and its potential benefits and burdens. The clinician who opts to take on this responsibility must provide the depth of content and time required to ensure that the patient can make an informed testing choice.”

Qualitative and quantitative research studies indicate that families hold a variety of beliefs about the inheritance of characteristics within families; some of these beliefs are congruent with current scientific understanding, whereas others are not. These beliefs may be influenced by education, personal and family experiences, and cultural background. Because behavior is likely to be influenced by these beliefs, the usefulness of genetic information may depend on recognizing and addressing the individual’s preexisting cognitions. This process begins with initial discussion and continues throughout the genetic counseling process.

Psychological Impact of Genetic Information/Test Results on the Individual

An accurate assessment of psychosocial functioning and emotional factors related to testing motivation and potential impact and utilization is an important part of pretest counseling. Generally, a provider inquires about a person’s emotional response to the family history of cancer and also about a person’s response to his or her own risk of developing cancer. People have various coping strategies for dealing with stressful circumstances such as genetic risk. Identifying these strategies and ascertaining how well or poorly they work will have implications for the support necessary during posttest counseling and will help personalize the discussion of anticipated risks and benefits of testing. Taking a brief history of past and current psychiatric symptoms (e.g., depression, extreme anxiety, or suicidality) will allow for an assessment of whether this individual is at particular risk of adverse effects following disclosure of results. In such cases, further psychological assessment may be indicated.

In addition, cognitive deficits in the person being counseled may significantly limit understanding of the genetic information provided and hinder the ability to give informed consent and may also require further psychological assessment. Emotional responses to cancer risk may also affect overall mood and functioning in other areas of life such as home, work, and personal health management, including cancer screening practices. Education and genetic counseling sessions provide an ongoing opportunity for informal assessment of affective and cognitive aspects of the communication process. Since behavioral factors influence adherence to screening and surveillance recommendations, consideration of emotional barriers is important in helping a person choose prevention strategies and in discussing the potential utility of genetic testing.

The discussion of issues such as history of depression, anxiety, and suicidal thoughts or tendencies requires sensitivity to the individual. The individual must be assured that the counseling process is a collaborative effort to minimize intrusiveness while maximizing benefits. Determining whether the individual is currently receiving treatment for major psychiatric illness is an important part of the counseling process. Consultation with a mental health professional familiar with psychological assessments may be useful to help the provider develop the strategies for these discussions. It also may be beneficial for the individual to be given standard psychological self-report instruments that assess levels of depression, anxiety, and other psychiatric difficulties that he or she may be experiencing. This step provides objective comparisons with already established normative data.

In addition to the clinical assessment of psychological functioning, several instruments for cancer patients and people at increased risk of cancer have been utilized to assess psychological status. These include the Center for Epidemiological Studies-Depression scale, the Profile of Mood States, the Hospital Anxiety and Depression Scale, and the Brief Symptom Inventory. Research programs have included one or more of these instruments as a way of helping refine the selection of people at increased risk of adverse psychosocial consequences of genetic testing. Psychological assessments are an ongoing part of genetic counseling. Some individuals with symptoms of increased distress, extreme avoidance of affect, or other marked psychiatric symptoms may benefit from a discussion with, or evaluation by, a mental health professional. It may be suggested to some people (generally, a very small percentage of any population) that testing be postponed until greater emotional stability has been established.

Psychological Impact of Genetic Information/Test Results on the Family

In addition to making an assessment of the family history of cancer, the family as a social system may also be assessed as part of the process of cancer genetic counseling. Hereditary susceptibility to cancer may affect social interactions and attitudes toward the family.

In assessing families, characteristics that may be relevant are the organization of the family (including recognition of individuals who propose to speak for or motivate other family members), patterns of communication within the family, cohesion or closeness of family members (or lack thereof), and the family beliefs and values that affect health behaviors. Ethnocultural factors may also play an important role in guiding behavior in some families.

Assessment also evaluates the impact of the family’s prior experience with illness on their attitudes and behaviors related to genetic counseling and testing. Prior experience with cancer diagnosis and treatment, loss due to cancer, and the family members’ interaction with the medical community may heavily influence attitudes toward receiving genetic information and may play a major role in the emotional state of individuals presenting for genetic services.

The practitioner may use the above framework to guide inquiries about the relationship of the individual to (1) the affected members of the family or (2) others who are considering or deciding against the consideration of genetic counseling or testing. Inquiries about how the family shares (or does not share) information about health, illness, and genetic susceptibility may establish whether the individual feels under pressure from other family members or anticipates difficulty in sharing genetic information obtained from counseling or testing. Inquiries about the present health (new diagnoses or deaths from cancer) or relationship status (divorce, marriage, grieving) of family members may inform the provider about the timing of the individual’s participation in counseling or testing and may also reveal possible contraindications for testing at present.

In addition to using a pedigree to evaluate family health history, tools such as the genogram and ecomap can provide specific information regarding the nature of interpersonal relationships within the family and the connections with social networks outside of the family.

Evidence from a study of 297 persons from 38 Lynch syndrome–affected families suggested that the timing of genetic counseling and testing services may influence psychological test-related distress responses. Specifically, family members in the same generation as the index case were more likely to experience greater test-related distress with increasingly longer lengths of time between the index case's receipt of MMR mutation results and the provision of genetic counseling and testing services to family members. However, it was unclear whether time lapses were due to a delay in the index case communicating test results or the family member choosing to delay genetic testing, despite being aware of the index case’s results.

More specific information about family functioning in coping with hereditary cancers can be found in the psychosocial or counseling sections of PDQ summaries on the genetics of specific types of cancer. (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer and Genetics of Colorectal Cancer for more information.)

Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing

There is substantial evidence that many people do not understand the potential limitations of genetic testing and may give too much weight to the potential benefits. Counseling provides the opportunity to present a balanced view of the potential risks and benefits of testing and to correct misconceptions. It may be helpful to ask individuals to identify their perceptions about the pros and cons of testing as part of this discussion.

Posttest education and result notification

The primary component of the posttest session is result notification. An individual may change his or her mind about receiving results, however, until the moment of results disclosure. Therefore, one typically begins the disclosure session by confirming that test results are still desired. Some people may decline or delay receipt of test results. The percentage of people who will make this decision is unknown. Such people need ongoing follow-up and the opportunity to receive test results in the future.

Once confirmed, people appreciate direct, immediate reporting of the results; they often describe the wait for results as one of the most stressful aspects of undergoing testing. Often, people need a few minutes of privacy to gather their composure after hearing their test results. Sometimes this precludes all but the briefest discussion at the initial posttest visit. Usually, individuals who have been properly prepared through the pretest counseling process do not exhibit disabling distress. Although it is rare that an acute psychological reaction will occur at disclosure, it is useful for providers of genetic test results to establish a relationship with a mental health provider who can be consulted should extreme reactions occur or who can be available by referral for people seeking further exploration of emotional issues.

Either at the time of disclosure or shortly thereafter, a session for the provider and the individual to consider the genetic, medical, psychological, and social ramifications of the test result is advisable. Despite having extensive pretest education, people may still be confused about the implications and meaning of the test results. Examples of frequently documented misconceptions include the belief that a positive result means that cancer is present or certain to develop; the belief that a negative result means that cancer will never occur; and failure to understand the uncertainty inherent in certain test results, as when only a limited mutation panel was examined. Regarding medical implications, it is important to inform the person of risk implications and management options for all of the cancer types associated with an inherited syndrome and to revisit options for risk management.

Posttest counseling may include consideration of the implications of the test results for other family members. It has been suggested that some individuals affected by an inherited disorder agree to have genetic testing performed in order to acquire information that could be shared with family members. There is evidence that implementation of a follow-up counseling program with the index patient, after test results are revealed, will significantly increase the proportion of relatives informed of their genetic risk. Follow-up counseling may include telephone conversations with the index patient verifying which family members have been contacted and an offer to assist with conveying information to family members. Some experts have suggested that if a test result is positive, plans should be made at this time for the notification, education, and counseling of other relatives based on the test result of the individual. Written materials, brochures, or personal letters may aid people in informing the appropriate relatives about genetic risk.

When a test result is negative, the posttest session may be briefer. It is important, however, to discuss genetic, medical, and psychological implications of a negative result in a family with a known mutation. For example, it is essential that the person understand that the general population risks for relevant cancer types still apply and that the person’s individual risk of cancer may still be influenced by other risk factors and family history from the other side of the family. Furthermore, people may be surprised to feel distress even when a test is negative. This outcome has been documented in the context of BRCA1/2 mutation testing and may also be anticipated in other cancer susceptibility testing. Posttest results discussion of such distress may lead to referral for additional counseling in some cases.

Many individuals benefit from follow-up counseling and consultation with medical specialists after disclosure of test results. This provides an opportunity for further discussion of feelings about their risk status, options for risk management including screening and detection procedures, and implications of the test results for other family members.


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Ethical, Legal, and Social Implications

Having an understanding of the ethical, legal, and social implications (ELSI) regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. This section discusses biomedical ethics codes, legal and social issues relevant to privacy, and fair use in the interpretation of genetic information. In order to integrate the different perspectives of bioethics, law, and psychosocial influences, case scenarios are offered to illustrate dilemmas encountered in the clinical setting. (Refer to the Determining the Test to Be Used section of this summary for more information about the regulation of genetic tests.)

Bioethical Issues in Cancer Genetic Testing

Bioethical tenets can guide health care providers in dealing with the complex issues surrounding predictive testing for hereditary cancer. The tenets of beneficence, nonmaleficence, autonomy, and justice are part of a framework needed to balance the complex and potentially conflicting factors surrounding a clinician’s role in respecting privacy, confidentiality and fair use of genetic information obtained from cancer genetic testing.

Beneficence

The concept of beneficence dictates that the primary goal of medical care is to provide benefit through appropriate health care. In the field of oncology, this translates into using early detection and effective treatment protocols to improve outcomes. Providing beneficent care may go beyond medical outcomes of treatment to encompass the patient’s life circumstances, expectations, and values. Consideration of the patient’s psychological and emotional ability to handle the testing and results disclosure process can help avoid doing harm. (Refer to the Psychological Impact of Genetic Testing/Test Results on the Individual section of this summary for more information.)

Nonmaleficence

Nonmaleficence is the bioethical code that directs health care providers to do no harm, inclusive of physical and emotional harm, and acknowledges that medical care involves risks and benefits. Particular to the field of oncology, adherence to this construct includes taking measures to minimize the adverse effects of cancer prevention, treatment, and control. This may encompass taking precautionary measures to prevent inadvertent disclosure of sensitive information.

Autonomy

Autonomous decision making respects individual preferences by incorporating informed consent and education. Individuals have the right to be informed about the risks and benefits of genetic testing and to freely choose or decline testing for themselves. Additionally, it is beneficial to consider the sociocultural context and family dynamics to ensure medical decision making takes places without coercion or interference.

Justice

Justice refers to the equitable distribution of the benefits and risks of health care. A goal in oncology is ensuring access to cancer genetic services. The availability of predictive genetic testing should not be dependent on ethnic background, geographical location, or ability to pay. Genetic discrimination should not be a result of predictive testing. Equitable distribution balances individual rights with responsibilities of community membership.

Privacy and Confidentiality: Disclosure of Patient’s Genetic Information

A strong provider-patient relationship is founded on respect for the patient’s privacy and confidentiality; therefore, protecting the patient’s personal information from third parties is key to building trust. Predictive testing for cancer susceptibility presents a challenge because of the hereditary nature of the diseases being tested and the implications of genetic risk for family members. Physicians are faced with a duty to warn or to act to prevent foreseeable harm. One practical suggestion for facilitating family-based communication is providing patients with education and information materials to facilitate disease susceptibility discussions with family members. The next section discusses the legal, legislative, and ethical basis for balancing patient confidentiality with duty to warn.

Disclosure in research

Privacy and confidentiality also applies to research, such as population screening for genetic diseases. The U.S. Department of Health and Human Services authorizes the use of Certificates of Confidentiality to researchers. This certificate, issued by the National Institutes of Health, protects the researcher from having to reveal the identity of any research subject “in any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings.” The protections offered by the certificate of confidentiality are limited to personally identifiable information collected beginning on the date of issuance and ending on the expiration date, which matches the date of study completion. The NIH Office of Extramural Research policy and guidance on Certificates of Confidentiality notes that any personally identifiable information collected during that time interval is protected in perpetuity. In regard to family-based recruitment strategies, the Cancer Genetics Network Bioethics Committee assembled a group of experts to develop recommendations for researchers to use in approaching family members. Due to the wide spectrum of research strategies, there are different levels of concern. Essential to family-based recruitment strategies is informing potential research participants how their personal information was obtained by the researcher, why the researcher is approaching them, what the researcher knows about them, and for what purpose the information will be used, whether or not they decide to participate.

“Duty to warn”: Legal proceedings, federal/state legislation, and recommendations of professional organizations

“Duty to warn” requires balancing the bioethical constructs of beneficence and autonomy with other factors such as case proceedings, legislation, and professional societies’ recommendations. As of September 2008, the National Council of State Legislatures lists the states that have legislation requiring consent to disclose genetic information. The definition of "genetic information" can vary depending on the legal case and the language used in state and federal legislation, and generally includes genetic testing and family history information; however, the definition generally does not apply to current diagnoses. Genetic diagnosis can be done through direct genetic tests (direct mutation analysis) for disorders linked to a specific gene and indirect genetic tests (indirect mutation analysis) for disorders in which the specific genes are not known or there are multiple different genes involved (genetic heterogeneity). There are four state case laws that apply to duty to warn. Two cases deal directly with testing for hereditary cancer predisposition syndromes; one case deals with a psychotherapist's duty to warn a relative of imminent threat, and another with genetic testing as a tool for reproductive decisions. Table 2 summarizes the cases.

At the federal level, there are strict nondisclosure policies governing private health information. The Standards for Privacy of Individually Identifiable Health Information (Privacy Rule), which summarizes the Health Insurance Portability and Accountability Act (HIPAA) of 1996, finds it permissible to disclose health information without consent when the public interest is at risk; therefore, under certain conditions, there are exceptions to the nondisclosure policy include the following:

Professional societies and government advisory agencies have published their different positions and recommendations on communication between a physician and a patient's relatives in regard to disclosure of genetic disease.

The Council on Ethical and Judicial Affairs of the American Medical Association (AMA) and the American Society of Clinical Oncology (ASCO) encourage discussing the importance of patients sharing genetic information with family members. Specifically, the Council on Ethical and Judicial Affairs of the American Medical Association states that “Physicians …should identify circumstances under which they would expect patients to notify biological relatives of the availability of information related to risk of disease…(and) physicians should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.” ASCO’s position is that providers “should remind patients of the importance of communicating test results to family members… ASCO believes that the cancer care provider’s obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit.” These organizations recommend that family members disclose genetic information.

The National Society of Genetic Counselors and the International Society of Nurses in Genetics support the release of any genetic information upon request to third parties including relatives but only with the patient's consent. One of the tenets of genetic counseling is to maintain information received from clients as confidential, unless released by the client or consent for disclosure is provided as required by law.

Similar to the Privacy Rule, the U.S. Bioethics Commission, American Society of Human Genetics, and National Human Genome Research Institute (NHGRI) recommend the following guidelines to identify exceptional circumstances under which it is ethically acceptable to breach confidentiality.

At an international level, the World Health Organization and World Medical Association have similar guidelines. Additionally, Australia, Canada, Germany, Japan, the Netherlands, and the United Kingdom have guidelines supporting the disclosure of genetic information to relatives under similar exceptional circumstances.

Employment and Insurance Discrimination

Genetic information obtained from genetic susceptibility tests may have medical, economic, and psychosocial implications for the individual tested and his or her family members. Employment and insurance discrimination are common concerns for individuals considering genetic testing. A review of ethical controversies in cancer genetics clinics included a phone interview of over 300 members of genetics support groups;13% of the study participants reported being denied or dismissed from a job, and 22% reported being refused life insurance because of a genetic disorder in the family.

Few empiric studies have documented the occurrence of insurance, employment, or other discrimination based on genetic test results for hereditary cancer syndromes. A study published in 2000 (8 years prior to the passage of the federal Genetic Information Nondiscrimination Act [GINA]) concluded that the use of information regarding presymptomatic genetic testing in health insurance underwriting decisions rarely, if ever, occurred either before or after the passage of state laws prohibiting such discrimination. Findings in this study were based on interviews with 29 genetic counselors, 5 patient advocates, 12 insurance regulators, 35 representatives of insurers, and 30 insurance agents.

In a smaller study of 47 unaffected BRCA or mismatch repair mutation carriers, a few instances of denial or limitation of life and health insurance benefits were reported following genetic testing; however, it was not possible to determine whether these adverse effects were directly related to the results of genetic testing. Nonetheless, a subset of mutation carriers reported that they paid for genetic testing out-of-pocket to avoid possible insurance discrimination (32%), had relatives who did not have genetic testing because of discrimination concerns (13%), and expressed reluctance to seek new job opportunities because of concerns about insurance coverage (13%).

A 2007 survey of members of the National Society of Genetic Counselors' (NSGC) Cancer Special Interest Group found that 94% perceived the risk of genetic discrimination to be low, very low, or theoretical. Most reported that they felt very or somewhat confident in the ability of U.S. federal and state laws (64% and 70%, respectively) to protect against genetic discrimination for cancer predisposition testing. Most disagreed that there are problems with health insurance as a result of having genetic testing, either for a person with (93%) or without (79%) a cancer diagnosis. The results of this study suggest that genetic counselors, who are on the forefront or providing risk assessment and counseling for hereditary cancers, may perceive the risk of genetic discrimination to be low and believe that existing state and federal laws offer adequate protection. Nonetheless, 35% of the NSGC sample agreed that patients may decline genetic testing for hereditary cancer risk because of concerns about health insurance discrimination. In addition, all respondents reported discussing genetic discrimination with some proportion of their patients, and 87% reported that they offer reassuring information about genetic discrimination to their patients.

(Refer to the Informed Consent and Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing subsections of this summary for more information about discrimination issues related to cancer genetics services.)

Legal proceedings, federal/state legislation, and recommendations of professional organizations

A legal case example at the federal district court level involves the Burlington Northern Santa Fe Railroad. The U.S. Equal Employment and Opportunities Commission requested that Burlington Northern Santa Fe Railroad not be allowed to use medical information obtained from genetic tests for employment decisions.

In the last 15 years, state and federal legislation statutes have been developed to prevent the use of genetic information for employment practices, such as hiring, promotion, and salary decisions; and insurance policies, including life and health coverage, by employers, schools, government agencies, and insurers. According to Executive Order 13145, federal departments and agencies are prohibited from discriminating against employees on the basis of genetic testing results or information about a request for genetic testing services. Employers and insurers are prohibited from intentionally lowering policy rates by using practices such as screening for individuals who are at risk of becoming ill or dying due to genetic disease susceptibility, such as cancer. Federal laws, including GINA, do not cover employer-provided life and disability; however, some states do have legislation addressing the use of genetic information for life and disability policies. The National Conference of State Legislatures (NCSL) summarized current health legislation of the U.S. Congress. Examples of relevant legislation regarding genetic information include, GINA, HIPAA, Americans with Disabilities Act (ADA), and Employee Retirement Income Security Act (ERISA).

Genetic Information Nondiscrimination Act 2008

GINA 2008 protects the provision of health insurance and employment against discrimination based on genetic information as follows:

  • Prohibits access to individuals’ personal genetic information by insurance companies and by employers.
  • Prohibits insurance companies from requesting that applicants for group or individual health coverage plans be subjected to genetic testing or screening and prohibits them from discriminating against health plan applicants based on individual genetic information.
  • Does not prohibit medical underwriting based on current health status.
  • Does not mandate coverage for medical tests or treatments.
  • Does not interfere or limit treating health care providers, including those employed or affiliated with health plans, from requesting or notifying individuals about genetic tests.
  • Prohibits employers from using genetic information to refuse employment, and prohibits them from collecting employees’ personal genetic information without their explicit consent.
  • Prohibits employment agencies from failing or refusing to refer a candidate on the basis of genetic information.
  • Prohibits labor organizations from refusing membership based on a member's genetic make-up.
  • Does not prohibit occupational testing for toxic monitoring programs, employer-sponsored wellness programs, administration of federal and state Family and Medical Leave Laws, and certain cases of inadvertent acquisition of genetic information.

GINA amends and/or extends coverage of HIPAA, ADA, and ERISA by including genetic information under medical privacy and confidentiality legislation and employment and insurance determinations. Additionally, with the passage of GINA, researchers and clinicians can encourage participation in clinical trials and appropriate genetic testing knowing that there are federal protections against discrimination based on the results of genetic testing. GINA established the minimum protection level that must be met in all states. However, for states with more robust legislation in place, GINA does not weaken existing protections provided by state law.

However, GINA has several limitations.

Exception to protections against employment and insurance discrimination: Active duty military personnel

GINA and other state and federal protections do not extend to genetic testing of active duty military personnel or genetic information obtained from active duty military personnel. In the military, genetic testing provides medical information that is to be used to protect military personnel from harmful duty or other exposures that could stimulate or aggravate a health problem. For example, use of certain antimalaria medication in individuals with glucose 6-phosphate dehydrogenase deficiency can result in red blood cell rupture. Therefore, some genetic information is critical for maintaining the health and safety of military personnel, given the possible stressful occupational environments they face. In addition, all military personnel provide a DNA sample to be maintained in a repository that can be used for identification purposes.

Results of genetic tests for disease predisposition could influence military eligibility for new enlistments, and for current military personnel, genetic test results could influence worldwide eligibility, assignments, and promotions. For example, a young woman found to carry a BRCA mutation may not be considered eligible for deployment for 12-15 months because access to recommended health care may not be easily accessible, such as breast MRI, a recommended screening modality for BRCA mutation carriers. Active duty military personnel with less than eight years of active duty service are especially vulnerable in the event they become disabled and must go before the medical board to establish benefit eligibility.

In 2006, Department of Defense Instruction Number 1332.38 (DODINST 1332.38) redefined preexisting condition as a result of two cases brought by service members who each had a hereditary condition that presented later in their military careers. The disability instructions state that any injury or disease discovered after a service member enters active duty—with the exception of congenital and hereditary conditions—is presumed to have been incurred in the line of duty. Any hereditary and/or genetic disease shall be presumed to have been incurred prior to entry into active duty. However, DODINST 1332.38 further states that any aggravation of that disease, incurred in the line of duty, beyond that determined to be due to natural progression, shall be deemed service aggravated. As a result of these two cases, the 8-year active duty service limit was established. This means that after 8 or more years of military service, the natural progression of a genetic condition would be deemed aggravated by military service. Therefore, until late 2008, the presence of a congenital or hereditary condition would not be considered a preexisting condition in disability decision making for those with 8 or more years of service.

In October 2008, in response to the National Defense Authorization Act of 2008 (NDAA) Title XVI: “Wounded Warrior Matters,” a policy memorandum was issued providing supplemental and clarifying guidance on implementing disability-related provisions, including new language related to hereditary or genetic diseases. The policy memorandum states, “Any hereditary or genetic disease shall be evaluated to determine whether clear and unmistakable evidence demonstrates that the disability existed before the Service member’s entrance on active duty and was not aggravated by military service. However, even if the conclusion is that the disability was incurred prior to entry on active duty, any aggravation of that disease, incurred while the member is entitled to basic pay, beyond that determined to be due to natural progression shall be determined to be service aggravated.” The interpretation of this policy is uncertain at this time.

Case scenarios involving ELSI issues in cancer genetic testing

There are multiple psychosocial, ethical, and legal issues to consider in cancer genetic testing. Genetic tests for germline mutations have social and family implications. In addition to prevention and surveillance options, genetic testing should be offered in conjunction with genetic education and counseling. A comprehensive strategy for dealing with ethical dilemmas can incorporate a shared approach to decision making, including open discussion, planning, and involvement of the family. To integrate the different perspectives of bioethics, law, and psychosocial influences, the following scenarios can help health care providers become familiar with commonly encountered dilemmas; it is imperative, however, that the clinician evaluate each patient and his or her situation on a case-by-case basis. These case scenarios were adopted from “Counseling about Cancer: Strategies for Genetic Counseling;” the in-depth case examples are extensively discussed in the original text.

Duty to warn versus privacy

A patient with known family history of breast cancer is interested in testing for BRCA1 and BRCA2 mutation. In reviewing her family history, the health care provider realizes that the patient is not aware of an additional rare but hereditary cancer mutation in a second-degree relative, which the health center tested and confirmed in the past. After talking with her family, the patient is unable to confirm the details of the second hereditary cancer mutation and again expresses interest in BRCA1/2 testing. Does the health care provider have a “duty to warn” the patient of the unknown cancer susceptibility gene in the family, at the risk of disclosing private patient information? The following issues are important to consider in resolving this case.

Patient’s right to know versus family member’s autonomy

A patient with a family history of a hereditary cancer is interested in predictive genetic testing and convinces an affected family member, who initially expresses unwillingness, to be tested in order to establish the familial mutation. In this scenario, the surviving family member admits to feeling pressured into consenting for genetic testing. Both the patient and the affected family member are patients. What takes precedence — the patient’s right to know or the family member’s autonomy? The following issues are important to consider in resolving this case.

Right to know versus right not to know

A hereditary cancer syndrome has been identified in a family. Within that family, an adult child wants a cancer susceptibility test that her parent declined, and one identical twin wants testing but the other does not. Even though the noninterested parties have declined testing and do not want to know the results, it is possible that testing one relative can disclose results for the other family members. Do the rights of the family members interested in predictive testing take precedence over the rights of the relatives who do not want to know? The following issues are important to consider in resolving this case.

Beneficence versus paternalism

A psychological assessment of a patient interested in predictive testing for an autosomal dominant cancer reveals a history of depression and suicidal attempts. The health care provider is considering denying or deferring testing because of concerns for the patient’s emotional well-being even though the patient refuses a referral to a psychologist because he reports feeling emotionally stable. Is deferring or denying predictive genetic testing a beneficent gesture or an act of paternalism? The following issues are important to consider in resolving this case.

Professional guidelines and other resources

(Refer to the Genetic Resources section of the Cancer Genetics Overview summary for more information about the ELSI of genetic testing and counseling.)


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Changes to This Summary (07/23/2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Cancer Risk Assessment and Counseling

Added text about a study of 1,181 California physicians and nurse practitioners that examined knowledge gaps and perceptions about cancer genetic testing, genetic discrimination, and genetic nondiscrimination laws.

Education and Counseling About Risk/Risk Communication

Added text to state that the receipt of genetic feedback for BRCA1/2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated (cited Voorwinden et al. as reference 28).

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.


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