2025
Genomic Landscape of Late-Stage Gastric Cancer: Analysis From KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Studies
Janjigian Y, Cecchini M, Shitara K, Enzinger P, Wainberg Z, Chau I, Satoh T, Lee J, Nebozhyn M, Loboda A, Kobie J, Vajdi A, Shih C, Cristescu R, Cao Z. Genomic Landscape of Late-Stage Gastric Cancer: Analysis From KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Studies. JCO Precision Oncology 2025, 9: e2400456. PMID: 40117530, PMCID: PMC11949223, DOI: 10.1200/po-24-00456.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedExome SequencingFemaleGenomicsHumansMaleMicrosatellite InstabilityMiddle AgedNeoplasm StagingStomach NeoplasmsConceptsTumor mutational burdenHomologous recombination deficiencyMicrosatellite instability-highGenomic characteristicsChromosomal instabilityKEYNOTE-062Late-stage GCKEYNOTE-059KEYNOTE-061Molecular subtypesAsian originWhole-exome sequencingGastric cancerSubtype prevalenceEpstein-Barr virus-positiveHomologous recombination deficiency scoresPretreatment tumor samplesWES dataGene expression signaturesCancer Genome AtlasMicrosatellite instability-high subtypeRNA sequencingGenomic landscapeEarly-stage GCGenomic alterationsRecessive genetic contribution to congenital heart disease in 5,424 probands
Dong W, Jin S, Sierant M, Lu Z, Li B, Lu Q, Morton S, Zhang J, López-Giráldez F, Nelson-Williams C, Knight J, Zhao H, Cao J, Mane S, Gruber P, Lek M, Goldmuntz E, Deanfield J, Giardini A, Mital S, Russell M, Gaynor J, Cnota J, Wagner M, Srivastava D, Bernstein D, Porter G, Newburger J, Roberts A, Yandell M, Yost H, Tristani-Firouzi M, Kim R, Seidman J, Chung W, Gelb B, Seidman C, Lifton R, Brueckner M. Recessive genetic contribution to congenital heart disease in 5,424 probands. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2419992122. PMID: 40030011, PMCID: PMC11912448, DOI: 10.1073/pnas.2419992122.Peer-Reviewed Original ResearchConceptsRecessive genotypeCHD probandsCongenital heart diseaseAssociated with laterality defectsGene-based analysisAnalyzed whole-exome sequencingLeft-sided congenital heart diseaseWhole-exome sequencingCongenital heart disease phenotypeAshkenazi Jewish probandsOffspring of consanguineous unionsSingle-cell transcriptomicsCHD geneExome sequencingMouse notochordSecreted proteinsConsanguineous familyFounder variantGenesSignificant enrichmentLaterality phenotypesHeart diseaseProbandsAbnormal contractile functionConsanguineous unionsModeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis.
Ward T, Morton S, Venturini G, Tai W, Jang M, Gorham J, Delaughter D, Wasson L, Khazal Z, Homsy J, Gelb B, Chung W, Bruneau B, Brueckner M, Tristani-Firouzi M, DePalma S, Seidman C, Seidman J. Modeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis. Journal Of The American Heart Association 2025, 14: e036860. PMID: 40028843, DOI: 10.1161/jaha.124.036860.Peer-Reviewed Original ResearchConceptsLoss-of-functionCongenital heart diseaseChromatin accessibilityMissense variantsCHD probandsPluripotent stem cellsHomozygous loss-of-functionCHD-associated genesHeterozygous loss-of-functionTranscription factor bindingMutant induced pluripotent stem cellsChromatin immunoprecipitation dataChromatin peaksStem cellsChromatin interactionsInduced pluripotent stem cellsFactor bindingTranscription factor NanogExome sequencingImmunoprecipitation dataTranscription factorsRNA sequencingChromatinMissenseMolecular consequencesProspective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
Biswas D, Liu Y, Herrero J, Wu Y, Moore D, Karasaki T, Grigoriadis K, Lu W, Veeriah S, Naceur-Lombardelli C, Magno N, Ward S, Frankell A, Hill M, Colliver E, de Carné Trécesson S, East P, Malhi A, Snell D, O’Neill O, Leonce D, Mattsson J, Lindberg A, Micke P, Moldvay J, Megyesfalvi Z, Dome B, Fillinger J, Nicod J, Downward J, Szallasi Z, Hackshaw A, Jamal-Hanjani M, Kanu N, Birkbak N, Swanton C. Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma. Nature Cancer 2025, 6: 86-101. PMID: 39789179, PMCID: PMC11779643, DOI: 10.1038/s43018-024-00883-1.Peer-Reviewed Original ResearchConceptsLung adenocarcinomaStage I diseaseClinicopathological risk factorsSurvival of patientsResponse to treatmentRNA sequencing dataI diseaseSequence dataMetastatic clonesNeedle biopsyIndividual tumorsLung expressionTranscription signalsPrognostic informationWhole exomeExpressed genesChemotherapy sensitivityProspective validationSurvival associationsTranscriptomic heterogeneityHuman tumorsEvolutionary measuresChromosomal instabilityRisk factorsNatural historyCoupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits
Scherer N, Fässler D, Borisov O, Cheng Y, Schlosser P, Wuttke M, Haug S, Li Y, Telkämper F, Patil S, Meiselbach H, Wong C, Berger U, Sekula P, Hoppmann A, Schultheiss U, Mozaffari S, Xi Y, Graham R, Schmidts M, Köttgen M, Oefner P, Knauf F, Eckardt K, Grünert S, Estrada K, Thiele I, Hertel J, Köttgen A. Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. Nature Genetics 2025, 57: 193-205. PMID: 39747595, PMCID: PMC11735408, DOI: 10.1038/s41588-024-01965-7.Peer-Reviewed Original ResearchConceptsWhole-exome sequencing dataGene-metabolite associationsHuman traitsHuman metabolic reactionsSequence dataAllelic seriesGene functionExome sequencingFunctional variantsGenetic studiesInborn errors of metabolismHeterozygous variantsErrors of metabolismMusculoskeletal traitsMetabolic reactionsHuman heightUrine metabolitesHeterozygous stateSulfate reabsorptionInborn errorsTraitsAggregation testVariantsHuman metabolismMetabolomics
2024
Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer
Hartwich T, Mansolf M, Demirkiran C, Greenman M, Bellone S, McNamara B, Nandi S, Alexandrov L, Yang‐Hartwich Y, Coma S, Pachter J, Santin A. Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer. Cancer Medicine 2024, 13: e70210. PMID: 39240189, PMCID: PMC11378359, DOI: 10.1002/cam4.70210.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzamidesCarcinoma, EndometrioidCell Line, TumorCell ProliferationEndometrial NeoplasmsExome SequencingFemaleFocal Adhesion Kinase 1HumansImidazolesMiceNeoplasm GradingOxazepinesProtein Kinase InhibitorsPyrazinesSulfonamidesXenograft Model Antitumor AssaysConceptsFocal adhesion kinaseWhole-exome sequencingEndometrial cancer cell linesVS-4718Cell linesRas/MAPK pathwayPhosphorylated focal adhesion kinaseWestern blot assayWhole-exome sequencing resultsRAF/MEK inhibitionEAC cell linesBlot assayP-FAKGenetic landscapeCell cycleEndometrial cancerGenetic derangementsDefactinibP-MEKGrowth inhibitionRAF/MEKRas/MAPKCell viabilityP-ERKHigh-grade endometrial cancerRare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes
Olfson E, Farhat L, Liu W, Vitulano L, Zai G, Lima M, Parent J, Polanczyk G, Cappi C, Kennedy J, Fernandez T. Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes. Nature Communications 2024, 15: 5870. PMID: 38997333, PMCID: PMC11245598, DOI: 10.1038/s41467-024-50247-7.Peer-Reviewed Original ResearchConceptsDNA sequencesRisk genesHigh-confidence risk genesWhole-exome DNA sequencingSequencing of familiesIdentified de novoLysine demethylase 5BDNA variantsTrio cohortBiological pathwaysGenesSequencing cohortGenetic factorsChildhood neurodevelopmental disordersAttention-deficit/hyperactivity disorderSequenceVariantsADHD riskNeurodevelopmental disordersKDM5BDNAMutationsFamilyLysineDiscoveryUnraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan
Azab B, Aburizeg D, Shaaban S, Ji W, Mustafa L, Isbeih N, Al-Akily A, Mohammad H, Jeffries L, Khokha M, Lakhani S, Al-Ammouri I. Unraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan. Scientific Reports 2024, 14: 15141. PMID: 38956129, PMCID: PMC11219879, DOI: 10.1038/s41598-024-64921-9.Peer-Reviewed Original ResearchConceptsExome sequencingSarcomere-related genesMitochondrial-related diseasesAt-risk family membersGenetic architectureGenetic landscapePathogenic variantsGene panelPediatric cardiomyopathyMolecular underpinningsGenetic testingPhenocopiesSarcomeric cardiomyopathiesGenesSequenceStorage disorderFamily membersAt-riskVariantsEarly interventionExomeFamilyGlycogen storage disorderHypertrophic cardiomyopathyCardiomyopathyIdentification of rare genetic variants in the PCDH genetic family in a cohort of transgender women
Theisen J, Chorich L, Xu H, Knight J, Kim H, Layman L. Identification of rare genetic variants in the PCDH genetic family in a cohort of transgender women. F&S Science 2024, 5: 283-292. PMID: 38942387, DOI: 10.1016/j.xfss.2024.06.005.Peer-Reviewed Original ResearchMeSH KeywordsAdultCadherinsCohort StudiesExome SequencingFemaleGender IdentityGenetic VariationHumansMaleProtocadherinsTransgender PersonsConceptsIdentification of rare genetic variantsRare genetic variantsDatabase for AnnotationGenetic variantsExome sequencingSanger sequencingTransgender womenCisgender menPlasma membrane adhesion moleculesGenetic familiesFunctional classification analysisGene family membersIntegrated Discovery toolMembrane adhesion moleculesVariant confirmationPcdh genesGene familyPcdhRare variantsGene variantsDiscovery analysisExomeSequenceSangerGenesUnilateral focal palmoplantar keratoderma associated with a postzygotic variant in PIK3CA and activation of the PI3K/AKT/mTOR pathway.
Gong Z, Peng S, Wang H, Jiang X, Ke X, Lin Z. Unilateral focal palmoplantar keratoderma associated with a postzygotic variant in PIK3CA and activation of the PI3K/AKT/mTOR pathway. European Journal Of Dermatology 2024, 34: 287-293. PMID: 39015962, DOI: 10.1684/ejd.2024.4704.Peer-Reviewed Original ResearchConceptsFocal palmoplantar keratodermaLaser capture microdissectionIdentified missense variantsPalmoplantar keratodermaWhole-exome sequencingMissense variantsGenomic DNASomatic variantsGenetic basisSanger sequencingMolecular dockingPostzygotic variantsBiological processesPI3K/AKT/mTOR pathwayPhenotypic heterogeneityEpidermal nevusPatient's peripheral bloodCongenital overgrowth disorderVariantsPIK3CASequencePeripheral bloodPI3K/Akt/mTOR signalingAffected epidermisOvergrowth disorderPersistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene
Atzmony L, Zagairy F, Mawassi B, Shehade M, Tatour Y, Danial-Farran N, Khayat M, Warrour N, Dodiuk-Gad R, Cohen-Barak E. Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene. JAMA Dermatology 2024, 160: 518-524. PMID: 38536168, PMCID: PMC10974685, DOI: 10.1001/jamadermatol.2024.0152.Peer-Reviewed Original ResearchConceptsSomatic variantsATP2A2 geneDeep sequencingResponse to environmental factorsCopy number variantsRestriction fragment length polymorphismLoss of heterozygosityWhole-exome sequencingChromosomal microarray analysisDarier's diseaseFragment length polymorphismPaired whole exome sequencingPathogenic germline variantsHeterozygous pathogenic germline variantsDD lesionsGenomic characteristicsGenetic analysisGenetic skin disordersGermline variantsSanger sequencingLength polymorphismSkin lesionsTransient lesionsHeterozygous variantsMicroarray analysisLoss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation
Jiang X, Yang C, Wang Z, Liang L, Gong Z, Huang S, Xu Z, Zhang B, Pei X, Cai L, Wang H, Lin Z. Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. British Journal Of Dermatology 2024, 191: 107-116. PMID: 38489583, DOI: 10.1093/bjd/ljae108.Peer-Reviewed Original ResearchConceptsLoss-of-function variantsMNT-1 cellsMinigene assaySkin hyperpigmentationGlomuvenous malformationsSkin lesionsUpregulation of microphthalmia-associated transcription factorSmall interfering RNA assaysMicrophthalmia-associated transcription factorDonor splice siteGeneralized skin hyperpigmentationWhole-exome sequencingProportion of stage IIIPhosphorylated p70S6KHyperpigmented skin disordersHyperpigmented skin lesionsSplice siteSplicing alterationsGenetic basisGenetic heterogeneityTranscription factorsSanger sequencingUnrelated familiesPremelanosome proteinSkin melanogenesisWhole-exome sequencing in UK Biobank reveals rare genetic architecture for depression
Tian R, Ge T, Kweon H, Rocha D, Lam M, Liu J, Singh K, Levey D, Gelernter J, Stein M, Tsai E, Huang H, Chabris C, Lencz T, Runz H, Chen C. Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression. Nature Communications 2024, 15: 1755. PMID: 38409228, PMCID: PMC10897433, DOI: 10.1038/s41467-024-45774-2.Peer-Reviewed Original ResearchMeSH KeywordsBiological Specimen BanksDepressionExome SequencingGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansConceptsGenome-wide association studiesRare coding variantsWhole-exome sequencingGenetic architectureGenetic relationshipsLoss-of-function intolerant genesContribution of rare coding variantsRare damagingAssociated with risk of depressionElectronic health recordsUK Biobank participantsPolygenic risk scoresRisk of depressionAssociated with riskIntolerant genesRisk lociAssociation studiesCoding variantsBiobank participantsHealth recordsUK BiobankDepression definitionsDepression riskBurden analysisRare variantscnnImpute: missing value recovery for single cell RNA sequencing data
Zhang W, Huckaby B, Talburt J, Weissman S, Yang M. cnnImpute: missing value recovery for single cell RNA sequencing data. Scientific Reports 2024, 14: 3946. PMID: 38365936, PMCID: PMC10873334, DOI: 10.1038/s41598-024-53998-x.Peer-Reviewed Original ResearchMeSH KeywordsCluster AnalysisExome SequencingGene Expression ProfilingProbabilityRNASequence Analysis, RNASingle-Cell AnalysisConceptsScRNA-seqAdvent of single-cell RNA sequencingScRNA-seq data analysisSingle cell RNA sequencing dataSingle-cell RNA sequencingRNA sequencing dataConvolutional neural networkSequence dataRNA sequencingCellular diversityExpression valuesCNN-based modelsMissing valuesCell clustersNeural networkIntricate diseaseIssue of missing dataSuperior performanceMissing probabilitySequenceBenchmark experimentsDiversityData analysisExpression
2023
A novel homozygous nonsense variant of AK7 is associated with multiple morphological abnormalities of the sperm flagella
Chang T, Tang H, Zhou X, He J, Liu N, Li Y, Xiang W, Yao Z. A novel homozygous nonsense variant of AK7 is associated with multiple morphological abnormalities of the sperm flagella. Reproductive BioMedicine Online 2023, 48: 103765. PMID: 38492416, DOI: 10.1016/j.rbmo.2023.103765.Peer-Reviewed Original ResearchConceptsHomozygous nonsense variantMultiple morphological abnormalitiesWhole-exome sequencingSperm flagellaAssociated with multiple morphological abnormalitiesMitochondrial function of spermatozoaFlagella-associated proteinsFunction of spermatozoaPotential gene variantsMitochondrial metabolic dysfunctionSperm ultrastructureFlagellar assemblyPatient's spermatozoaFlagellar defectsRate of apoptosisConcentration of reactive oxygen speciesMale infertilitySanger sequencingReactive oxygen speciesMitochondrial functionSpermSpermatozoaMutated genesFunctional associationDisease phenotypePrimary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene
Fernandez T, Williams Z, Kline T, Rajendran S, Augustine F, Wright N, Sullivan C, Olfson E, Abdallah S, Liu W, Hoffman E, Gupta A, Singer H. Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene. PLOS ONE 2023, 18: e0291978. PMID: 37788244, PMCID: PMC10547198, DOI: 10.1371/journal.pone.0291978.Peer-Reviewed Original ResearchConceptsRisk genesDe novo damaging variantsGene expression patternsWhole-exome DNA sequencingMid-fetal developmentAdditional risk genesHigh-confidence risk genesParent-child triosGene OntologyCell signalingExpression patternsCalcium ion transportFunctional convergenceCell cycleDamaging variantsGenesDNA sequencingDe novoASD probandsGenetic etiologyBiological mechanismsSequencingDNANetwork analysisIon transportToward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing
Erdogan O, Özkaya Ş, Erzik C, Bilguvar K, Arga K, Bayraklı F. Toward Precision Oncology in Glioblastoma with a Personalized Cancer Genome Reporting Tool and Genetic Changes Identified by Whole Exome Sequencing. OMICS A Journal Of Integrative Biology 2023, 27: 426-433. PMID: 37669106, DOI: 10.1089/omi.2023.0117.Peer-Reviewed Original ResearchMeSH KeywordsDNA Copy Number VariationsExome SequencingGlioblastomaHumansPhosphatidylinositol 3-KinasesPrecision MedicineConceptsTreatment optionsWhole-exome sequencingPrecision/personalized medicineExome sequencingLimited treatment optionsGenetic alterationsPersonalized medicinePotential therapeutic targetAggressive brain tumorTumor tissue samplesPoor prognosisGBM patientsTargetable pathwaysBrain tumorsTherapeutic targetLarger studyMolecular findingsNeurosurgical oncologyGenomic profilingPatientsPersonalized therapyMolecular profilingAkt/GlioblastomaPrecision oncologyAdvancing diagnosis and management of liver disease in adults through exome sequencing
Zheng M, Hakim A, Konkwo C, Deaton A, Ward L, Genetics A, Silveira M, Assis D, Liapakis A, Jaffe A, Jiang Z, Curry M, Lai M, Cho M, Dykas D, Bale A, Mistry P, Vilarinho S. Advancing diagnosis and management of liver disease in adults through exome sequencing. EBioMedicine 2023, 95: 104747. PMID: 37566928, PMCID: PMC10433007, DOI: 10.1016/j.ebiom.2023.104747.Peer-Reviewed Original ResearchConceptsLiver diseaseWhole-exome sequencingUnknown etiologyTertiary referral academic medical centerReferral academic medical centerExome sequencingLiver disease patientsManagement of adultsAcademic health care centerComprehensive clinical evaluationHealth care centersAcademic medical centerGenetic variantsRare genetic variantsAdult patientsLiver centersHepatic steatosisDisease patientsClinical evaluationCare centerFamily historyMedical CenterClinical valueAdult medicinePatientsPLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsIntegrated exome sequencing and microarray analyses detected genetic defects and underlying pathways of hepatocellular carcinoma
Chong M, Knight J, Peng G, Ji W, Chai H, Lu Y, Wu S, Li P, Hu Q. Integrated exome sequencing and microarray analyses detected genetic defects and underlying pathways of hepatocellular carcinoma. Cancer Genetics 2023, 276: 30-35. PMID: 37418972, DOI: 10.1016/j.cancergen.2023.06.002.Peer-Reviewed Original ResearchConceptsTumor mutation burdenWhole-exome sequencingGrade IIIHepatocellular carcinomaCNA burdenCase seriesBarcelona Clinic Liver Cancer stageExome sequencingBCLC stage CLiver Cancer stageEdmondson-Steiner gradingLarge case seriesGenetic defectsHigher CNA burdenAdjacent nontumor tissuesΒ-catenin pathwayBetter prognosisClinicopathologic findingsPoor prognosisClinicopathologic classificationCancer stageSurvival statusMutation burdenStage CPrognostic prediction
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