2025
Possible role of mosaic mutations of neurodevelopmental disorder-related genes in bipolar disorder: Lessons from Kmt2c chimeric heterozygous knockout mice
Nakamura T, Nakajima K, Fujimori-Tonou N, Kasahara T, Tsuboi T, Kato T. Possible role of mosaic mutations of neurodevelopmental disorder-related genes in bipolar disorder: Lessons from Kmt2c chimeric heterozygous knockout mice. Neuroscience Research 2025, 217: 104910. PMID: 40414358, DOI: 10.1016/j.neures.2025.05.005.Peer-Reviewed Original ResearchBipolar disorderSpectrum of bipolar disordersAutism-like phenotypeAutism spectrum disorderAutism-like behaviorsDepression-like episodesKnockout miceMosaic mutationsHeterozygous knockout miceMental disordersSpectrum disorderKleefstra syndromeGenetic architecture of bipolar disorderDisordersSymptomatic spectrumAnxietyExome sequencing analysisGenetic architectureSequence analysisCausative genesMosaic miceGenesSomatic mutationsAutismKMT2CAPOBEC affects tumor evolution and age at onset of lung cancer in smokers
Zhang T, Sang J, Hoang P, Zhao W, Rosenbaum J, Johnson K, Klimczak L, McElderry J, Klein A, Wirth C, Bergstrom E, Díaz-Gay M, Vangara R, Colon-Matos F, Hutchinson A, Lawrence S, Cole N, Zhu B, Przytycka T, Shi J, Caporaso N, Homer R, Pesatori A, Consonni D, Imielinski M, Chanock S, Wedge D, Gordenin D, Alexandrov L, Harris R, Landi M. APOBEC affects tumor evolution and age at onset of lung cancer in smokers. Nature Communications 2025, 16: 4711. PMID: 40394004, PMCID: PMC12092836, DOI: 10.1038/s41467-025-59923-8.Peer-Reviewed Original ResearchConceptsLung cancerTumor evolutionMulti-omics profilingLung tumor samplesCell of originProgenitor-like cellsMulti-OmicsMutagenic processesMutational processesOff-target activityTP53 mutationsMutational burdenSignaling pathwayKRAS mutationsMutagenesisAPOBEC mutagenesisSomatic mutationsSolid tumorsTumor samplesClonal expansionDNA damageTumor developmentCell typesMutationsStemness markersLuck gone cold: A trifecta of B cell mutations associates with cryoglobulinemia.
Chen K, O'Connor K. Luck gone cold: A trifecta of B cell mutations associates with cryoglobulinemia. Science Immunology 2025, 10: eadx6827. PMID: 40184441, DOI: 10.1126/sciimmunol.adx6827.Peer-Reviewed Original ResearchConceptsAutoreactive B cellsSomatic mutationsAssociated with cryoglobulinemiaB cellsMutationsAutoimmune diseasesThe interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease
Vilarinho S. The interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease. Nature Genetics 2025, 57: 775-776. PMID: 40169790, DOI: 10.1038/s41588-025-02151-z.Peer-Reviewed Original Research110 Characterization of Frequency and Spectrum of PIK3CA Somatic Mutations in Advanced Breast Cancer
Amraei R, Kahn A, Walther Z, Finberg K, Gibson J, Kahila M. 110 Characterization of Frequency and Spectrum of PIK3CA Somatic Mutations in Advanced Breast Cancer. Laboratory Investigation 2025, 105: 102334. DOI: 10.1016/j.labinv.2024.102334.Peer-Reviewed Original ResearchGenomic alterations in normal breast tissues preceding breast cancer diagnosis
Dai J, Rozenblit M, Li X, Shan N, Wang Y, Mane S, Marczyk M, Pusztai L. Genomic alterations in normal breast tissues preceding breast cancer diagnosis. Breast Cancer Research 2025, 27: 60. PMID: 40264151, PMCID: PMC12013151, DOI: 10.1186/s13058-025-02018-5.Peer-Reviewed Original ResearchConceptsHistologically normal breast tissueSomatic mutationsNormal breast tissueGenomic alterationsBreast tissuePre-DiagnosisMethodsWhole exome sequencingCancer diagnosisCancer predisposition genesCOSMIC signature 3Breast cancerCancer hallmark genesBreast tissue of womenBreast cancer diagnosisEvading growth suppressorsVariant burdenMutational signature analysisRegulatory genesAffected genesExome sequencingGermline variantsTissue of womenTissues adjacent to cancerDNA repairGenomic instability
2024
SINGLE-CELL ANALYSIS OF SOMATIC MUTATIONS IN HUMAN LUNG REVEALS ASSOCIATION WITH TRANSCRIPTIONAL CHANGES IN AGING
De Man R, Adams T, McDonough J, Cala-Garcia J, Moss B, Yan X, Rosas I, Kaminski N. SINGLE-CELL ANALYSIS OF SOMATIC MUTATIONS IN HUMAN LUNG REVEALS ASSOCIATION WITH TRANSCRIPTIONAL CHANGES IN AGING. Innovation In Aging 2024, 8: 571-572. PMCID: PMC11690935, DOI: 10.1093/geroni/igae098.1872.Peer-Reviewed Original ResearchSomatic mutationsMutational burdenCell type annotationAlveolar type 1DNA damage response genesAnalysis of somatic mutationsSomatic mutation accumulationAccumulation of somatic mutationsCell typesUbiquitin ligase geneDamage response genesLoss of cell functionAnalyzed somatic mutationsDecreased expressionSingle-cell RNAseqLigase geneMutation accumulationTop genesSignaling GenesCell marker genesResponse genesTranscriptional changesAlveolar type 1 cellsGenesMarker genesColibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer
Agrawal R, Al-Hiyari S, Hugh-White R, Hromas R, Patel Y, Williamson E, Mootor M, Gonzalez A, Fu J, Haas R, Jordan M, Wickes B, Mohammed G, Tian M, Doris M, Jobin C, Wernke K, Pan Y, Yamaguchi T, Herzon S, Boutros P, Liss M. Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer. European Urology Oncology 2024, 8: 716-730. PMID: 39547899, PMCID: PMC12075626, DOI: 10.1016/j.euo.2024.10.015.Peer-Reviewed Original ResearchProstate cancerInduction of genomic instabilityPC diagnosisPC etiologyColibactin-producing Escherichia coliEtiology of prostate cancerProstate cancer cellsProstate cancer diagnosisSomatic point mutationsCombination in vitroGenomic instabilityAndrogen-dependentColon cancerPatient populationProstateClinical cohortInitial cancerSomatic mutationsCancer cellsDihydrotestosteroneGenetic dysfunctionSingle cell lineCancerCell linesDiagnosisMitochondrial Heteroplasmy Is a Novel Predictor of Chronic Lymphocytic Leukemia Risk
Pasca S, Hong Y, Shi W, Puiu D, Lake N, Lek M, Guallar E, Arking D, Gondek L. Mitochondrial Heteroplasmy Is a Novel Predictor of Chronic Lymphocytic Leukemia Risk. Blood 2024, 144: 4054-4054. DOI: 10.1182/blood-2024-210250.Peer-Reviewed Original ResearchMitochondrial heteroplasmyClonal hematopoiesis of indeterminate potentialMtDNA heteroplasmyWhole-exome sequencing dataSomatic mutationsPresence of somatic mutationsExome sequencing dataCancer-associated genesClonal hematopoiesisClonal expansionVariant allele frequencyAssociated with myeloid malignanciesMtDNA variantsMitochondrial DNAPresence of mutationsSequence dataUK Biobank (UKBBiologically significant roleDeleterious mutationsHeteroplasmyChronic lymphocytic leukemia riskAllele frequenciesOncogenic transformationMitochondrial functionMyeloid genesSomatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury E, Jones A, Seplyarskiy V, Nguyen T, Rosenbluh C, Bae T, Wang Y, Abyzov A, Khoshkhoo S, Chahine Y, Zhao S, Venkatesh S, Root E, Voloudakis G, Roussos P, Network B, Park P, Akbarian S, Brennand K, Reilly S, Lee E, Sunyaev S, Walsh C, Chess A. Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes. Science 2024, 386: 217-224. PMID: 39388546, PMCID: PMC11490355, DOI: 10.1126/science.adq1456.Peer-Reviewed Original ResearchConceptsTranscription Factor Binding SitesWhole-genome sequencingOpen chromatinMutational processesSomatic mutationsFactor binding sitesSchizophrenia casesSchizophrenia risk genesSomatic mosaicismSomatic variantsRisk genesG mutationGene expressionGermline mutationsBinding sitesGenesMutationsIncreased somatic mutationsChromatinMosaic somatic mutationsPrenatal neurogenesisContext of schizophreniaBrain neuronsSchizophrenia brainVariantsSteering research on mRNA splicing in cancer towards clinical translation
Anczukow O, Allain F, Angarola B, Black D, Brooks A, Cheng C, Conesa A, Crosse E, Eyras E, Guccione E, Lu S, Neugebauer K, Sehgal P, Song X, Tothova Z, Valcárcel J, Weeks K, Yeo G, Thomas-Tikhonenko A. Steering research on mRNA splicing in cancer towards clinical translation. Nature Reviews Cancer 2024, 24: 887-905. PMID: 39384951, PMCID: PMC11698124, DOI: 10.1038/s41568-024-00750-2.Peer-Reviewed Original ResearchSplicing aberrationsMRNA splicingLong-read RNA sequencingRNA sequencingShort-read RNA sequencingCopy number variationsMis-spliced transcriptsRecurrent somatic mutationsSynthetic lethal approachSingle-cell levelSpliceosome componentsSplicing alterationsSplicing factorsCellular processesNumber variationsSpliceosome inhibitorsMRNA isoformsDNA repairSplicingSomatic mutationsTumor vulnerabilitiesLethal approachHuman cancersCancer initiationCancer progressionRisk prediction for clonal cytopenia: multicenter real-world evidence
Xie Z, Komrokji R, Al Ali N, Regelson A, Geyer S, Patel A, Saygin C, Zeidan A, Bewersdorf J, Mendez L, Kishtagari A, Zeidner J, Coombs C, Madanat Y, Chung S, Badar T, Foran J, Desai P, Tsai C, Griffiths E, Al Malki M, Amanam I, Lai C, Deeg H, Ades L, Arana Yi C, Osman A, Dinner S, Abaza Y, Taylor J, Chandhok N, Soong D, Brunner A, Carraway H, Singh A, Elena C, Ferrari J, Gallì A, Pozzi S, Padron E, Patnaik M, Malcovati L, Savona M, Al-Kali A. Risk prediction for clonal cytopenia: multicenter real-world evidence. Blood 2024, 144: 2033-2044. PMID: 38996210, PMCID: PMC11561536, DOI: 10.1182/blood.2024024756.Peer-Reviewed Original ResearchMyeloid neoplasmsIncidence of MNClonal cytopeniaCumulative incidencePlatelet count <High-risk mutationsCox proportional hazards modelsVariant allele fractionProportional hazards modelClinical trial designCCUS patientsStratify patientsGray's testC-indexDisease entityRisk groupsCytopeniasAllele fractionSomatic mutationsRisk factorsHigh riskNatural historyRisk scoreHazards modelPatientsA newly identified gene Ahed plays essential roles in murine haematopoiesis
Nakai R, Yokota T, Tokunaga M, Takaishi M, Yokomizo T, Sudo T, Shi H, Yasumizu Y, Okuzaki D, Kokubu C, Tanaka S, Takaoka K, Yamanishi A, Yoshida J, Watanabe H, Kondoh G, Horie K, Hosen N, Sano S, Takeda J. A newly identified gene Ahed plays essential roles in murine haematopoiesis. Nature Communications 2024, 15: 5090. PMID: 38918373, PMCID: PMC11199565, DOI: 10.1038/s41467-024-49252-7.Peer-Reviewed Original ResearchConceptsMutant embryonic stem cellsConditional knockoutUncharacterised genesHaematopoietic cellsNuclear proteinsFunctional genesHaematopoiesis in vivoAssociated with malignancyBiological functionsGenesSomatic mutationsEmbryonic stem cellsHaematopoietic developmentTransplantation experimentsHaematological malignanciesDeletionAdult miceCancer patientsCoordinated actionEmbryonic dayStem cellsHaematopoiesisMurine haematopoiesisCellsMalignancyAssociation of Somatic TET2 Mutations With Giant Cell Arteritis
Robinette M, Weeks L, Kramer R, Agrawal M, Gibson C, Yu Z, Sekar A, Mehta A, Niroula A, Brown J, McDermott G, Reshef E, Lu J, Liou V, Chiou C, Natarajan P, Freitag S, Rao D, Ebert B. Association of Somatic TET2 Mutations With Giant Cell Arteritis. Arthritis & Rheumatology 2024, 76: 438-443. PMID: 37909388, PMCID: PMC10922498, DOI: 10.1002/art.42738.Peer-Reviewed Original ResearchConceptsGiant cell arteritisClonal hematopoiesisHematologic malignanciesTET2 mutationsVision lossSomatic TET2 mutationsClinical phenotypes of giant cell arteritisDevelopment of giant cell arteritisGiant cell arteritis diagnosisAssociated with vision lossSomatic mutationsPresence of somatic mutationsIncident giant cell arteritisDevelopment of hematological malignanciesUKB participantsInfluence clinical outcomesMultivariate Cox regressionSomatic genetic testingPresence of mutationsElectronic health record reviewHealth record reviewUK Biobank (UKBGCA cohortClinical outcomesClonal mutationsPatterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia
Jain A, Ball S, Aguirre L, Al Ali N, Kaldas D, Tinsley-Vance S, Kuykendall A, Chan O, Sweet K, Lancet J, Padron E, Sallman D, Komrokji R. Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia. Haematologica 2024, 109: 2157-2164. PMID: 38299605, PMCID: PMC11215361, DOI: 10.3324/haematol.2023.283661.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaAcute myeloid leukemia transformationMulti-lineage dysplasiaAbsolute neutrophil countMyelodysplastic syndromeSomatic mutationsLR-MDSMyeloid leukemiaBone marrowLow-risk myelodysplastic syndromesHigh-risk myelodysplastic syndromeLow absolute neutrophil countLow riskHigh riskHigh bone marrowAssociated with less progressionLow platelet countHigh-risk diseaseLR-MDS patientsMDS patientsRinged sideroblastsRisk diseaseSF3B1 mutationsBM fibrosisPlatelet count
2023
Pairwise 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 exclusivityMore than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome
Minteer C, Thrush K, Gonzalez J, Niimi P, Rozenblit M, Rozowsky J, Liu J, Frank M, McCabe T, Sehgal R, Higgins-Chen A, Hofstatter E, Pusztai L, Beckman K, Gerstein M, Levine M. More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome. Science Advances 2023, 9: eadf4163. PMID: 37467337, PMCID: PMC10355820, DOI: 10.1126/sciadv.adf4163.Peer-Reviewed Original ResearchConceptsStem cell divisionImmortalized human cellsTissue-specific cancer riskTumorigenic stateCell divisionDNA methylationEpigenetic changesAge-related accumulationHuman cellsMultiple tissuesSomatic mutationsClinical tissuesTissue differencesEpigenomeCellsTissueNormal tissuesMethylationMutationsReplicationNormal breast tissueSignaturesVitroAccumulationDivisionA novel immune checkpoint score system for prognostic evaluation in pancreatic adenocarcinoma
Chen Y, Lin X, Zou X, Qian Y, Liu Y, Wang R, Wang X, Yu X, Liu C, Cheng H. A novel immune checkpoint score system for prognostic evaluation in pancreatic adenocarcinoma. BMC Gastroenterology 2023, 23: 113. PMID: 37024802, PMCID: PMC10080823, DOI: 10.1186/s12876-023-02748-w.Peer-Reviewed Original ResearchConceptsTumor-infiltrating immune cellsExpression of OX40Risk score modelImmune cellsIdentified OX40Immune checkpointsOverall survivalScoring systemRisk scoreClinical specimensExpression of immune checkpoint genesCD8+ T cellsImmune checkpoint gene expressionSomatic mutationsProtein expressionHigh-risk score groupImmunogenic cell deathCheckpoint gene expressionImmune checkpoint expressionImmune checkpoint genesImmune cell infiltrationNaive B cellsCox regression analysisAssociated with increased survival ratesRisk scoring systemInterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma
Orlow I, Sadeghi K, Edmiston S, Kenney J, Lezcano C, Wilmott J, Cust A, Scolyer R, Mann G, Lee T, Burke H, Jakrot V, Shang P, Ferguson P, Boyce T, Ko J, Ngo P, Funchain P, Rees J, O’Connell K, Hao H, Parrish E, Conway K, Googe P, Ollila D, Moschos S, Hernando E, Hanniford D, Argibay D, Amos C, Lee J, Osman I, Luo L, Kuan P, Aurora A, Rothberg BE, Bosenberg M, Gerstenblith M, Thompson C, Bogner P, Gorlov I, Holmen S, Brunsgaard E, Saenger Y, Shen R, Seshan V, Nagore E, Ernstoff M, Busam K, Begg C, Thomas N, Berwick M, Consortium O. InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma. PLOS ONE 2023, 18: e0269324. PMID: 37011054, PMCID: PMC10069769, DOI: 10.1371/journal.pone.0269324.Peer-Reviewed Original ResearchConceptsEarly-stage melanomaPrimary melanomaMemorial Sloan-Kettering Cancer CenterDisease-specific survivalPredictors of survivalMulti-institutional settingSomatic mutationsPre-established protocolMiRNA expressionScreening failureMulticenter studyCancer CenterDownstream testingLimited tumor tissueNucleic acid qualityClinical databaseMulticenter researchTumor tissueMelanomaTumor samplesFFPE tumorsArchival tissueFFPE tissue blocksTissue blocksSuccess rateEarly-Onset Colorectal Cancer Somatic Gene Mutations by Population Subgroups.
Shen X, DeWan A, Johnson C. Early-Onset Colorectal Cancer Somatic Gene Mutations by Population Subgroups. Cancer Discovery 2023, 13: 530-531. PMID: 36855917, DOI: 10.1158/2159-8290.cd-22-1464.Peer-Reviewed Original Research
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