Featured Publications
APOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma
Cannataro VL, Kudalkar S, Dasari K, Gaffney SG, Lazowski HM, Jackson LK, Yildiz I, Das RK, Rothberg BE, Anderson KS, Townsend JP. APOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma. Lung Cancer 2022, 171: 34-41. PMID: 35872531, PMCID: PMC10126952, DOI: 10.1016/j.lungcan.2022.07.004.Peer-Reviewed Original ResearchConceptsCytidine deaminationMutagenic processesDefective homologous recombinationGenomic sequencesHomologous recombinationAttractive potential targetAPOBEC mutagenesisLung squamous cell carcinomaDeamination activityCancer cell growthAPOBEC proteinsAPOBEC activityCell growthCellular proliferationNFE2L2MutationsMolecular investigationsCancer effectsPotential targetMolecular variantsAPOBECSurvival of cancerSquamous cell carcinomaDeaminationVariantsAttribution of Cancer Origins to Endogenous, Exogenous, and Preventable Mutational Processes
Cannataro VL, Mandell JD, Townsend JP. Attribution of Cancer Origins to Endogenous, Exogenous, and Preventable Mutational Processes. Molecular Biology And Evolution 2022, 39: msac084. PMID: 35580068, PMCID: PMC9113445, DOI: 10.1093/molbev/msac084.Peer-Reviewed Original ResearchConceptsBurden of cancerPublic health strategiesWhole-exome sequencingTobacco exposureLung cancerProstate adenocarcinomaBreast cancerCancer effectsHealth strategiesOncogenic driversCancer originCancer typesCancer cell lineagesCancerPathogen exposureExogenous mutational processesMajority of mutationsTumorsSingle nucleotide variantsPreventable processActivity accountsSurvivalOncogenic variantsCell lineagesProliferationHeavy mutagenesis by tobacco leads to lung adenocarcinoma tumors with KRAS G12 mutations other than G12D, leading KRAS G12D tumors—on average—to exhibit a lower mutation burden
Tan C, Mandell JD, Dasari K, Cannataro VL, Alfaro-Murillo JA, Townsend JP. Heavy mutagenesis by tobacco leads to lung adenocarcinoma tumors with KRAS G12 mutations other than G12D, leading KRAS G12D tumors—on average—to exhibit a lower mutation burden. Lung Cancer 2021, 166: 265-269. PMID: 34736794, DOI: 10.1016/j.lungcan.2021.10.008.Peer-Reviewed Original ResearchEnvironmental and sex-specific molecular signatures of glioma causation
Claus EB, Cannataro VL, Gaffney SG, Townsend JP. Environmental and sex-specific molecular signatures of glioma causation. Neuro-Oncology 2021, 24: 29-36. PMID: 33942853, PMCID: PMC8730771, DOI: 10.1093/neuonc/noab103.Peer-Reviewed Original ResearchConceptsIDH wild-type tumorsWild-type tumorsEnvironmental risk factorsIDH-mutant tumorsRisk factorsCases of gliomaMolecular signaturesPIK3CA mutationsPossible risk exposuresMutation subtypesCancer effectsExogenous exposureAdult gliomasTumorsWhole-exome sequencing dataGliomasKinase domainMutational signaturesCancer-causing mutationsMalesFemalesNon-coding regionsPIK3R1SexCancer mutational signaturesCancer Relevance of Human Genes
Qing T, Mohsen H, Cannataro VL, Marczyk M, Rozenblit M, Foldi J, Murray M, Townsend J, Kluger Y, Gerstein M, Pusztai L. Cancer Relevance of Human Genes. Journal Of The National Cancer Institute 2022, 114: 988-995. PMID: 35417011, PMCID: PMC9275765, DOI: 10.1093/jnci/djac068.Peer-Reviewed Original ResearchConceptsCore cancer genesHuman genesFunctional importanceSomatic mutation frequencySelection pressureGene/protein networksCancer genesHigher somatic mutation frequencyNegative selection pressureGene-gene interaction networksMutation frequencyProtein-truncating variantsGenomic contextCell viabilityGenes decreasesCancer Genome AtlasInteraction networksProtein networkCancer relevanceCancer cell viabilityCell survivalGenesCancer biologyGenome AtlasSearch toolsEstimation of neutral mutation rates and quantification of somatic variant selection using canceffectsizeR
Mandell J, Cannataro V, Townsend J. Estimation of neutral mutation rates and quantification of somatic variant selection using canceffectsizeR. Cancer Research 2022, 83: 500-505. PMID: 36469362, PMCID: PMC9929515, DOI: 10.1158/0008-5472.can-22-1508.Peer-Reviewed Original ResearchConceptsMutation rateEpistatic effectsSite-specific mutation ratesNeutral mutation rateNucleotide mutation ratePan-cancer datasetCancer cell survivalFunctional impact scoresCustom genomesPairwise epistasisSet of variantsHuman genomeR packageTranscriptomic dataSomatic variant dataModel of selectionSingle nucleotideCancer effectsCell survivalNucleotide mutationsCancer biologyVariant dataMutational signature analysisMutationsSomatic mutations
2022
Not only mutations but also tumorigenesis can be substantially attributed to DNA damage from reactive oxygen species in RUNX1::RUNX1T1-fusion-positive acute myeloid leukemia
Mandell J, Fisk J, Cyrenne E, Xu M, Cannataro V, Townsend J. Not only mutations but also tumorigenesis can be substantially attributed to DNA damage from reactive oxygen species in RUNX1::RUNX1T1-fusion-positive acute myeloid leukemia. Leukemia 2022, 36: 2931-2933. PMID: 36369483, PMCID: PMC9712081, DOI: 10.1038/s41375-022-01752-5.Peer-Reviewed Original ResearchA phylogenetic approach to study the evolution of somatic mutational processes in cancer
Miura S, Vu T, Choi J, Townsend JP, Karim S, Kumar S. A phylogenetic approach to study the evolution of somatic mutational processes in cancer. Communications Biology 2022, 5: 617. PMID: 35732905, PMCID: PMC9217972, DOI: 10.1038/s42003-022-03560-0.Peer-Reviewed Original ResearchConceptsMutational processesPattern of conservationFalse-positive discovery rateCollection of mutationsSomatic mutational processesPhylogenetic approachGenomic variationSomatic variationCell lineagesMutational signaturesTumor evolutionMutation signaturesPhylogenyCancer cellsDiscovery rateMutationsComputer-simulated datasetsRelative activityLineagesComputational methodsSignaturesConservationDivergenceEvolutionJoint analysis
2021
The somatic molecular evolution of cancer: Mutation, selection, and epistasis
Dasari K, Somarelli JA, Kumar S, Townsend JP. The somatic molecular evolution of cancer: Mutation, selection, and epistasis. Progress In Biophysics And Molecular Biology 2021, 165: 56-65. PMID: 34364910, PMCID: PMC8819680, DOI: 10.1016/j.pbiomolbio.2021.08.003.Peer-Reviewed Original ResearchConceptsCancer evolutionEpistatic interactionsNeutral mutation rateCancer progressionEvolution of neoplasmsSingle nucleotide variantsMolecular evolutionRate of fixationGenetic interactionsEvolutionary biologyPhylogenetic analysisCopy number aberrationsPhylogenetic relationsNeutral mutationsGenomic dataSelective pressureSynonymous mutationsMutation rateChromosomal instabilityPhenotypic changesLoss of heterozygosityFitness landscapeClonal deconvolutionTumor microenvironmentEnvironment interactionIdentifying modules of cooperating cancer drivers
Klein MI, Cannataro VL, Townsend JP, Newman S, Stern DF, Zhao H. Identifying modules of cooperating cancer drivers. Molecular Systems Biology 2021, 17: msb20209810. PMID: 33769711, PMCID: PMC7995435, DOI: 10.15252/msb.20209810.Peer-Reviewed Original ResearchConceptsCancer typesNRAS-mutant melanomaCombination of alterationsMultiple cancer typesClinical outcomesNFE2L2 mutationsIndividual patientsDriver alterationsEffective personalized treatmentPathway inhibitionTherapeutic potentialCancer etiologyPersonalized treatmentTumor formationTCGA cancer typesAlterationsPatientsCancer driversEtiologyMelanomaCancer
2019
Re: Ming-Jun Shi, Xiang-Yu Meng, Philippe Lamy, et al. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer. Eur Urol 2019;76:9–13
Yang A, Cannataro VL, Townsend JP. Re: Ming-Jun Shi, Xiang-Yu Meng, Philippe Lamy, et al. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer. Eur Urol 2019;76:9–13. European Urology 2019, 77: e24-e25. PMID: 31474441, PMCID: PMC7017921, DOI: 10.1016/j.eururo.2019.08.018.Commentaries, Editorials and LettersWagging the long tail of drivers of prostate cancer
Cannataro VL, Townsend JP. Wagging the long tail of drivers of prostate cancer. PLOS Genetics 2019, 15: e1007820. PMID: 30653503, PMCID: PMC6336235, DOI: 10.1371/journal.pgen.1007820.Commentaries, Editorials and LettersAPOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma
Cannataro VL, Gaffney SG, Sasaki T, Issaeva N, Grewal NKS, Grandis JR, Yarbrough WG, Burtness B, Anderson KS, Townsend JP. APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma. Oncogene 2019, 38: 3475-3487. PMID: 30647454, PMCID: PMC6499643, DOI: 10.1038/s41388-018-0657-6.Peer-Reviewed Original ResearchConceptsPositive selectionCancer phenotypeStrong positive selectionIntensity of selectionEffects of mutationsBasis of mutationsSomatic genetic variantsSomatic evolutionNeutral driftMutational processesAPOBEC mutagenesisBiochemical experimentsSelection intensityMolecular understandingCytosine basesIndividual substitutionsAPOBEC3B proteinMutant stateMutational signaturesGenetic variantsNeck squamous cell carcinomaMutationsE545KGene variantsPhenotype
2018
Effect Sizes of Somatic Mutations in Cancer
Cannataro VL, Gaffney SG, Townsend JP. Effect Sizes of Somatic Mutations in Cancer. Journal Of The National Cancer Institute 2018, 110: 1171-1177. PMID: 30365005, PMCID: PMC6235682, DOI: 10.1093/jnci/djy168.Peer-Reviewed Original ResearchConceptsSelection intensityRecurrent single nucleotide variantsCancer cell lineagesSomatic variantsSingle nucleotide variantsSequence surveysSomatic tissuesReproductive advantageCancer genomesDevelopment of cancerCell lineagesSelective advantageEvolutionary processesDriver genesNucleotide variantsCancer biologyGenetic alterationsSomatic mutationsCancer cellsRelative importanceCancer growthGenesMutationsCancer typesVariantsLvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira
Adhikarla H, Wunder EA, Mechaly AE, Mehta S, Wang Z, Santos L, Bisht V, Diggle P, Murray G, Adler B, Lopez F, Townsend JP, Groisman E, Picardeau M, Buschiazzo A, Ko AI. Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira. Frontiers In Cellular And Infection Microbiology 2018, 8: 45. PMID: 29600195, PMCID: PMC5863495, DOI: 10.3389/fcimb.2018.00045.Peer-Reviewed Original ResearchConceptsResponse regulatorTwo-component system proteinsDNA-binding response regulatorGlobal transcriptional regulationHybrid histidine kinaseGlobal gene regulationNovel signal pathwayComprehensive genomic analysisPhosphotransfer assaysTCS genesHistidine kinaseGene duplicationTranscriptional regulationGene regulationCorresponding genesPhylogenetic analysisGenomic analysisMolecular basisMutant strainSystem proteinsSignaling systemInfection processGenesBranched pathwayVirulenceSomatic evolutionary timings of driver mutations
Gomez K, Miura S, Huuki LA, Spell BS, Townsend JP, Kumar S. Somatic evolutionary timings of driver mutations. BMC Cancer 2018, 18: 85. PMID: 29347918, PMCID: PMC5774140, DOI: 10.1186/s12885-017-3977-y.Peer-Reviewed Original Research
2017
Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up
Kadara H, Choi M, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, Zhao Z, Behrens C, Fujimoto J, Chow C, Yoo Y, Kalhor N, Moran C, Rimm D, Swisher S, Gibbons DL, Heymach J, Kaftan E, Townsend JP, Lynch TJ, Schlessinger J, Lee J, Lifton RP, Wistuba II, Herbst RS. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Annals Of Oncology 2017, 28: 75-82. PMID: 27687306, PMCID: PMC5982809, DOI: 10.1093/annonc/mdw436.Peer-Reviewed Original ResearchConceptsRecurrence-free survivalPoor recurrence-free survivalWhole-exome sequencingEarly-stage lung adenocarcinomaMutant lung adenocarcinomaLung adenocarcinomaImmune markersClinical outcomesExact testNatural killer cell infiltrationProportional hazards regression modelsGranzyme B levelsImmune marker analysisImmune profiling analysisPD-L1 expressionImmune-based therapiesTumoral PD-L1Hazards regression modelsKRAS mutant tumorsNormal lung tissuesMajority of deathsFisher's exact testHigh mutation burdenAnalysis of immunophenotypeRelevant molecular markersMutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function
Choi M, Kadara H, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, Zhao Z, Behrens C, Fujimoto J, Chow C, Kim K, Kalhor N, Moran C, Rimm D, Swisher S, Gibbons DL, Heymach J, Kaftan E, Townsend JP, Lynch TJ, Schlessinger J, Lee J, Lifton RP, Herbst RS, Wistuba II. Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Annals Of Oncology 2017, 28: 83-89. PMID: 28177435, PMCID: PMC6246501, DOI: 10.1093/annonc/mdw437.Peer-Reviewed Original ResearchConceptsLung squamous cell carcinomaEarly stage lung squamous cell carcinomaNon-small cell lung cancerSquamous cell carcinomaWhole-exome sequencingImmune markersClinical outcomesCell carcinomaPIK3CA mutationsExact testPoor recurrence-free survivalProportional hazards regression modelsTumoral PD-L1 expressionPD-L1 expressionRecurrence-free survivalCell lung cancerComprehensive immune profilingTP53 mutant tumorsHazards regression modelsNormal lung tissuesFisher's exact testLUSC cohortAdjuvant therapyImmune profilingPoor prognosis
2016
PhyloOncology: Understanding cancer through phylogenetic analysis
Somarelli JA, Ware KE, Kostadinov R, Robinson JM, Amri H, Abu-Asab M, Fourie N, Diogo R, Swofford D, Townsend JP. PhyloOncology: Understanding cancer through phylogenetic analysis. Biochimica Et Biophysica Acta (BBA) - Reviews On Cancer 2016, 1867: 101-108. PMID: 27810337, PMCID: PMC9583457, DOI: 10.1016/j.bbcan.2016.10.006.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAdaptation, PhysiologicalAlgorithmsAnimalsBiomarkers, TumorCell Transformation, NeoplasticEvolution, MolecularGene Expression Regulation, NeoplasticGenetic FitnessGenetic Predisposition to DiseaseGenomicsHeredityHumansModels, GeneticMutationNeoplasmsPedigreePhenotypePhylogenySignal TransductionSystems BiologyTime FactorsConceptsDr. Robert A. GatenbyGenome-scale dataSystems biology approachPowerful systems biology approachUse of phylogeneticsPhylogenetic analysisBiology approachPhylogenetic applicationsSubclonal evolutionCancer biologyCancer progressionSuite of algorithmsPhylogeneticsCancer data setsCancer samplesImproved therapeutic interventionRobust approachDecades of researchFundamental insightsNew toolBiologyDiverse fieldsGatenbyData setsTherapeutic interventionsPathScore: a web tool for identifying altered pathways in cancer data
Gaffney SG, Townsend JP. PathScore: a web tool for identifying altered pathways in cancer data. Bioinformatics 2016, 32: 3688-3690. PMID: 27503224, DOI: 10.1093/bioinformatics/btw512.Peer-Reviewed Original Research