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

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S.Korean

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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