2023
Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
Xu C, Huang K, Law J, Chua J, Sheng T, Flores N, Pizzi M, Okabe A, Tan A, Zhu F, Kumar V, Lu X, Benitez A, Lian B, Ma H, Ho S, Ramnarayanan K, Anene-Nzelu C, Razavi-Mohseni M, Ghani S, Tay S, Ong X, Lee M, Guo Y, Ashktorab H, Smoot D, Li S, Skanderup A, Beer M, Foo R, Wong J, Sanghvi K, Yong W, Sundar R, Kaneda A, Prabhakar S, Mazur P, Ajani J, Yeoh K, So J, Tan P. Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities. Gut 2023, 72: 1651-1663. PMID: 36918265, DOI: 10.1136/gutjnl-2022-328332.Peer-Reviewed Original ResearchConceptsGastric cancerMolecular subtypesPromoter activityMutational signaturesProinflammatory tumor microenvironmentTumor microenvironmental changesMutated driver genesSingle-cell transcriptome profilingCTCF occupancyGC molecular subtypesChromatin profilingDistal enhancerRegulatory networksEpigenetic landscapeBRD4 bindingEpigenomic reprogrammingEpigenomic levelsTumor-intrinsicTumor inflammationTumor microenvironmentTherapeutic vulnerabilitiesTranscriptome profilingDriver genesNFkB inhibitorGene expression
2021
Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
Sheng T, Ho S, Ooi W, Xu C, Xing M, Padmanabhan N, Huang K, Ma L, Ray M, Guo Y, Sim N, Anene-Nzelu C, Chang M, Razavi-Mohseni M, Beer M, Foo R, Sundar R, Chan Y, Tan A, Ong X, Skanderup A, White K, Jha S, Tan P. Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer. Genome Medicine 2021, 13: 158. PMID: 34635154, PMCID: PMC8504099, DOI: 10.1186/s13073-021-00970-3.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationADP-Ribosylation FactorsCell Line, TumorCell ProliferationChromatinEnhancer Elements, GeneticEpigenomicsGene Expression Regulation, NeoplasticGenomicsHistonesHumansInhibitor of Growth Protein 1OncogenesPromoter Regions, GeneticRNA-SeqStomach NeoplasmsTranscriptomeWhole Genome SequencingConceptsSingle nucleotide polymorphismsActivity-by-contactEnhancer-promoter interactionsSomatic copy number alterationsGermline single nucleotide polymorphismsHistone modificationsDistal cis-regulatory elementsLow somatic mutation rateCell-specific gene expressionCis-regulatory elementsFunctional enhancer activityHistone modification profilesWhole-genome sequencingRegulatory region sequencingCell fate determinationSuper-enhancer regionsCopy number alterationsGenome copy numberEffect of histone acetylationSomatic mutation rateCancer-relevant genesFunctional assay dataEnhanced activityGC cell linesRegion sequencesEpigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
Sundar R, Huang K, Kumar V, Ramnarayanan K, Demircioglu D, Her Z, Ong X, Bin Adam Isa Z, Xing M, Tan A, Tai D, Choo S, Zhai W, Lim J, Thakur M, Molinero L, Cha E, Fasso M, Niger M, Pietrantonio F, Lee J, Jeyasekharan A, Qamra A, Patnala R, Fabritius A, De Simone M, Yeong J, Ng C, Rha S, Narita Y, Muro K, Guo Y, Skanderup A, So J, Yong W, Chen Q, Göke J, Tan P. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut 2021, 71: 1277-1288. PMID: 34433583, PMCID: PMC9185816, DOI: 10.1136/gutjnl-2021-324420.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitionImmune microenvironmentHuman immune systemCheckpoint inhibitionActive human immune systemGastric cancerHuman T-cell infiltrationT cell cytolytic activityResistance to immune checkpoint inhibitionImmune systemProgression-free survivalImmunotherapy-treated patientsT cell infiltrationTumor immune microenvironmentT cell proportionsImmune-editingImmunotherapy resistanceFunctional in vivo studiesTumor kineticsHumanised miceAlternative promoter useTumor microenvironmentTherapeutic responseCytolytic activityImmune depletion
2019
Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer
Sundar R, Huang K, Qamra A, Kim K, Kim S, Kang W, Tan A, Lee J, Tan P. Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer. Annals Of Oncology 2019, 30: 424-430. PMID: 30624548, PMCID: PMC6442650, DOI: 10.1093/annonc/mdy550.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitionMetastatic gastric cancerT cell cytolytic activityResistance to immune checkpoint inhibitionCheckpoint inhibitionGastric cancerCytolytic activityImmune evasionMedian progression-free survivalPhase II clinical trial of patientsCancer treated with immunotherapyClinical trials of patientsMechanisms of immune evasionResponse rateTreated with pembrolizumabPhase II clinical trialProgression-free survivalFresh tumor biopsiesPost-treatment biopsiesCohort of patientsTrial of patientsEarly gastric cancerArchival tissue samplesClinical responseTumor biopsies