Novel Driver Genes and Prognostic Mutation Signatures...
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Novel Driver Genes and Prognostic Mutation Signatures Identified by Genomic Analyses of Gastric Cancer Xiangchun Li, William KK Wu, Rui Xing, Sunny H. Wong, Kexin Chen, Huanming Yang, Wei Zhang, Matthew T.V. Chan, Youyong Lu, Joseph JY Sung, Jun Yu Oct. 26 th , 2015 at 23 rd UEG The authors declare no conflict of interest
Transcript of Novel Driver Genes and Prognostic Mutation Signatures...
NovelDriverGenesandPrognosticMutationSignaturesIdentifiedbyGenomicAnalysesof
GastricCancerXiangchun Li,WilliamKKWu,Rui Xing,SunnyH.Wong,Kexin Chen,Huanming Yang,WeiZhang,MatthewT.V.
Chan,Youyong Lu,JosephJYSung,JunYu
Oct. 26th, 2015at23rd UEGTheauthorsdeclarenoconflictofinterest
The analysis workflow
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Sourceofgenomicdata
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Published publications CohortChen K, Yang D, Li X, et al: Mutational landscape of gastric adenocarcinoma in Chinese : Implications for prognosis and therapy. Proc Natl Acad Sci 6:1–6, 2015
Tianjin China
Cancer T, Atlas G: Comprehensive molecular characterization of gastric adenocarcinoma. Nature , 2014 TCGAWang K, Yuen ST, Xu J, et al: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46:573–82, 2014 Hong KongWong SS, Kim K-M, Ting JC, et al: Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing. Nat Commun5:5477, 2014 S. KoreanKakiuchi M, Nishizawa T, Ueda H, et al: Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet 46:583–7, 2014 Japan
Stratification of GC accordingto mutation burdens
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Mutationspectrumof GC withdifferentmutationburdens
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Mutational signature deciphering
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Mutational signatures operativein gastric cancer
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Mutational signatures operativein gastric cancer
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Kernal PCA of mutational signatures
1st Principal Component
2nd
Prin
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S.Korean
TCGA
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Regular-mutatedHyper-mutated
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The importance of mutationalsignature in distinguishingbetween RGC and HGC
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The presence of mutationalsignatures
APOBEC signature mutation: TCW (whereW = A or T)11
The APOBEC signaturemutation
APOBEC signature mutation: TCW (whereW = A or T)12
Mutational landscape inregular-mutated GC
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Prognostic significance ofC1/2 in RGC
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Prognosis of C1/2 stratified byLauren’s classification
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Prognosticsignificance ofC1/2 in the 2nd
cohort
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Altered signalling pathways inregular-mutated GC
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Mutational landscape inhyper-mutated GC
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Prognosis of CDH1mutation indiffuse-/intestinal-typeGC
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Prognosis of CDH1mutation inthe 2nd diffuse-type GC cohort
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Conclusions
• There are ubiquitousandspecificmutationalprocessesunderlyingthepathogenesisofdifferentsubtypesofGCwithvaryingmutationburdens.
• SeveralnovelSMGsthataremutatedatintermediateorlowprevalencewereidentified.
• Regular-mutated GC canbefurtherstratifiedintotwosubtypes(i.e.C1/2)withdistinctclinicaloutcomes.
• CDH1 mutationisanindependentprognosticfactorforpoorersurvivalinpatientswithdiffuse-typeGC.
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Acknowledgement
• The Chinese University of Hong Kong (CUHK): WilliamKKWu, SunnyH.Wong, MatthewT.V.Chan, JosephJYSung and JunYu
• PekingUniversityCancerHospital&Institute: Rui Xing, YouyongLu• Beijing Genomics Institute (BGI): Xiaodong Fang, Mengyao Wang,Jiaqian Wang, Lin Li, Yong Zhou, KunlongQiu, LongyunChen and Dr.Huanming Yang
• MD AndersonCancer Center: Yuexin Liu and Wei Zhang• TianjinMedicalUniversityCancerInstituteandHospital: Kexin Chen
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StateKeyLaboratoryofDigestiveDisease
