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Centerpoint Summer 2010 (PDF)
Shedding light on sleep and cancer
Yong Zhu points to the fluorescent fixture above his desk. “That completely changed our lifestyle,” said Zhu, who is the co-Director of Cancer Prevention and Control Research Program at Yale Cancer Center and an Associate Professor of Epidemiology and Public Health. For most of human evolution, we woke up with the sun and slept at night. With the invention of the electric light, we could ignore the schedules our bodies have evolved to observe.
There were unintended consequences to burning the midnight oil. In the early 2000s, several studies established links between working the nightshift and some cancers. The strongest relationship was with breast cancer. In 2007, the World Health Organization named shift work as a probable carcinogen.
But this research could not tell us why shift workers had higher rates of cancer. Animal studies showed a link between malfunctions in circadian genes, the genes that regulate sleep cycles, and some cancers. Research findings in animals, however, often fail to translate to humans.
Zhu’s research provides a critical missing piece to the puzzle. “Our work makes a link between the gene and the human cancer,” explained Zhu. His group looked at all nine human core circadian genes in healthy volunteers and cancer patients. He found alterations in six of those genes were associated with breast cancer. He also determined eight circadian genes were associated with prostate cancer, and another four with non-Hodgkin’s lymphoma. Breast and prostate cancer are both affected by hormones; therefore Zhu suspects the circadian genes regulate hormones.
Zhu has proven there is a genetic susceptibility to some cancers through irregular circadian genes. But earlier studies tell us all shift workers are at risk for some of these same cancers. So what is to blame -- heredity or environment? Both, Zhu’s believes. “The interaction between genetics and lifestyle probably plays the most important role,” he said.
Proposed role of the circadian clock in tumorigenesis is illustrated in Figure 1.
The irregularities Zhu found associated with cancers were both genetic and epigenetic. In other words, some of the alterations were irregularities in the DNA, irregularities that are present at birth. Epigenetic changes, however, affect the way a cell functions without changing the structure of its DNA. Epigenetic changes may result from environmental exposures.
Zhu is looking at large population samples to find out if shift work conclusively causes epigenetic changes. He’s often crunching his data until 1 a.m., under that florescent light. For the purpose of his research, however, that’s not considered shift work. He’s looking at a large group of volunteers in Denmark who work the overnight shift.
Meanwhile, he’s continuing laboratory research to examine exactly what’s happening on a cellular level when altered circadian genes lead to the development of cancers. A clear understanding of the process will give medicine a chance to interrupt it – to engineer drugs that would be especially effective combating cancers associated with particular genes.
Shakespeare wrote about “sleep that knits up the raveled sleeve of care.” Zhu explains that circadian genes do knit up imperfections. They play a role in cellular repair functions. When these functions are working well, the body repairs faulty DNA or induces defective cells to die. The sleep-cancer connection may occur because that repair function is disrupted, leaving malignancies free to develop.
There are immediate practical uses for Zhu’s research. For example, someone carrying one of the circadian gene alterations associated with increased risk might choose a profession where daytime schedules are common.
That is increasingly difficult, however. Night hours were once associated with specific careers, such as healthcare, factory work, and some service industries. But according to the U.S. Bureau of Labor Statistics, more jobs are becoming night jobs. Globalism is creating a need for more white-collar workers to abandon their 9-to-5 schedules to interact with distant colleagues.
Zhu also found that alterations in certain circadian genes predict a patient’s risk of recurrence. This could be helpful information for patients and their oncologists when deciding how aggressively a cancer should be treated, he explained.
Zhu has begun publishing his landmark findings. Earlier this year, the press picked up on his discovery that alterations in the so-called CLOCK gene put women at higher risk for breast cancer. The effect was especially strong in women with estrogen- or progesterone-receptor negative tumors, which are typically aggressive.
“I began getting emails from all over the world,” Zhu said. Many were from women who worked night shifts and had been diagnosed with cancer. One came from a woman who works in a dark room and wondered whether her dim quarters put her at risk.
Zhu thinks that’s a good question and hopes to look at light exposure in future research. He was attracted to this work because of the enormous number of good questions it presents. Most circadian genes were discovered only within the past 10-20 years. Furthermore, the tools to analyze their actions on a molecular level continue to evolve. That provides tremendous promise to investigate circadian genes and by understanding them to devise better treatments and even prevention strategies for common cancers. “We’ve got a lot of work to do,” Zhu commented.