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 carcinomaDeaminationVariantsPairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis
Alfaro-Murillo J, Townsend J. Pairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis. Mathematical Biosciences 2023, 366: 109091. PMID: 37996064, PMCID: PMC10847963, DOI: 10.1016/j.mbs.2023.109091.Peer-Reviewed Original ResearchStrength of selectionEpistatic effectsSelection coefficientsMutation rateHigher-order epistatic effectsLarge mutation ratesLarge selection coefficientsSomatic cancer mutationsUncontrolled cell growthSomatic evolutionMultiple somatic mutationsDriver genesCancer mutationsCancer research communityGenesSomatic genotypeCell growthOncogenesisMutationsSomatic mutationsEvolutionary modelsConsequent trajectoriesCancer genotypesPersonalized cancer therapyMutual exclusivityEstimation 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
2024
Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia
Mandell J, Diviti S, Xu M, Townsend J. Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia. International Journal Of Molecular Sciences 2024, 25: 6589. PMID: 38928295, PMCID: PMC11203805, DOI: 10.3390/ijms25126589.Peer-Reviewed Original ResearchGenomic analysisPediatric acute lymphoblastic leukemiaCancer effectsAcute lymphoblastic leukemiaT cellsTherapeutic targetSomatic substitutionsRare driversB-ALLLymphoblastic leukemiaEpistatic effectsT-cell ALL patientsMutational contributionsMutated genesCancer phenotypeMutated formDevelopment of leukemiaLow prevalenceB-cell lineageDisease mechanismsMutationsPrecision therapeuticsTherapeutic opportunitiesT-ALLALL patients
2022
A 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
2020
Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden
Qing T, Mohsen H, Marczyk M, Ye Y, O’Meara T, Zhao H, Townsend JP, Gerstein M, Hatzis C, Kluger Y, Pusztai L. Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden. Nature Communications 2020, 11: 2438. PMID: 32415133, PMCID: PMC7228928, DOI: 10.1038/s41467-020-16293-7.Peer-Reviewed Original ResearchConceptsAge groupsGermline variantsSomatic mutationsLate-onset cancerEarly-onset cancersCancer hallmark genesSomatic mutation burdenMutation burdenMalignant transformationCancer genesYounger ageGermline alterationsCancerVariant burdenBurdenAverage numberHallmark genesAgeNegative correlationStrong negative correlationMutationsPatientsGroup
2019
APOBEC-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 typesVariantsAnalysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials
Wilkins JF, Cannataro VL, Shuch B, Townsend JP. Analysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials. Oncotarget 2018, 9: 22243-22253. PMID: 29854275, PMCID: PMC5976461, DOI: 10.18632/oncotarget.25155.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsStrength of selectionMutation rateSomatic variantsSynergistic epistasisAnalysis of mutationsDetailed mechanistic knowledgeGenetic architectureContribution of mutationsLineage selectionDrug development effortsEvolutionary principlesTherapeutic potentialDrug developmentMechanistic knowledgeEpistasisMutationsCancer typesVariant frequencyVariantsGenesSelectionClinical trialsPotential therapeutic benefitSubstantial clinical benefitRigorous guidance
2017
Distributions of Mutational Effects and the Estimation of Directional Selection in Divergent Lineages of Arabidopsis thaliana
Park B, Rutter MT, Fenster CB, Symonds VV, Ungerer MC, Townsend JP. Distributions of Mutational Effects and the Estimation of Directional Selection in Divergent Lineages of Arabidopsis thaliana. Genetics 2017, 206: 2105-2117. PMID: 28550014, PMCID: PMC5560809, DOI: 10.1534/genetics.116.199190.Peer-Reviewed Original ResearchConceptsMutation accumulation dataDirectional selectionNatural selectionMutational effectsPhenotypic traitsDirectional natural selectionQuantitative trait lociDivergent lineagesRosette diameterTrait lociHistorical selectionQuantitative traitsLineagesArabidopsisTraitsDensity traitsAccumulation dataDivergenceKey roleUltimate sourceLociSelectionOrganismsKey componentMutations
2016
Early and multiple origins of metastatic lineages within primary tumors
Zhao ZM, Zhao B, Bai Y, Iamarino A, Gaffney SG, Schlessinger J, Lifton RP, Rimm DL, Townsend JP. Early and multiple origins of metastatic lineages within primary tumors. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 2140-2145. PMID: 26858460, PMCID: PMC4776530, DOI: 10.1073/pnas.1525677113.Peer-Reviewed Original ResearchConceptsMetastatic lineagesGenetic changesEarly genetic divergenceMolecular evolutionary modelsSingle genetic changeDivergent lineagesTumor phylogeneticsDivergence timesAncestral stateGenetic divergenceCancer lineagesPhylogenetic analysisEvolutionary processesLineagesCancer evolutionMultiple originsDriver genesCancer biologyCancer progressionSomatic mutationsTumor developmentEvolutionary modelsDriver mutationsChronogramMutations
2012
Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance
Zhang Z, Li J, Cui P, Ding F, Li A, Townsend JP, Yu J. Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance. BMC Bioinformatics 2012, 13: 43. PMID: 22435713, PMCID: PMC3368730, DOI: 10.1186/1471-2105-13-43.Peer-Reviewed Original ResearchConceptsCodon usage biasNucleotide compositionUsage biasGenome evolutionGene functionProtein functionCodon usageNatural selectionCodon positionsTranslational efficiencySelective pressureSequence compositionGene expressionSequence analysisSimulated sequencesSequenceGenomeGenesFundamental importanceMutationsInformative estimationExpression