Comprehensive genomic

characterization of gastric cancer

Ph.D candidate: Xiangchun LI

Supervisor: Prof. Jun YU

Co-supervisor: William K.K. WU

2016/06/14

Cancer Statistics in China, 2015

2

1

2

3

1

2

3

4

4

WanqingChenetal.CancerstatisticsinChina,

2015

Risk factors for GC

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https://gi.jhsps.org

Age

Gender

H.pylori&

EBV

Smoking&

alcohol

Lifestyle

&diet

Familyhistory

&genetics

Race&

ethnicit

y

Multistep model of GC development

4

ManishA.ShahandDavidP.Kelsen

Lauren’sclassificationofgastriccancer(GC)

5

Ø Intestinal-type

generallywelldifferentiatedwithaglandularappearanceand

tendtoexpandthroughthestomachwall.

Ø Diffuse-type

morecommonlypoorlydifferentiatedandspreadassingle

discohesivecellsthatinfiltratethroughoutthestomachwall.

Molecular classification proposed by

TCGA Network

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TCGANetwork

Source of genomic data

8

Publications Cohort

1. Chen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

2. CancerT,AtlasG:Comprehensivemolecularcharacterizationofgastric

adenocarcinoma.Nature,2014 TCGA

3. Wang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Kong

4. WongSS,KimK-M,TingJC,etal:Genomiclandscapeandgeneticheterogeneityin

gastricadenocarcinomarevealedbywhole-genomesequencing.NatCommun

5:5477,2014 S.Korean

5. Kakiuchi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

What can we detect with NGS?

9

The analysis workflow

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Stratification of GC according to mutation burdens

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Mutation spectrum of GC with

different mutation burdens

12

An illustration of mutational

processes operative in human cancer

13

AdaptedfromHellendayT.et al.

Mutational signature deciphering

14

Mutational signatures operative

in gastric cancer

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Mutational signatures operative

in gastric cancer

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APOBEC signature responsible for PIK3CA

hotspot mutations in RGC

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TpCpW (W = A or T)

18

Hyper-

mutatedGC

The importance of mutational signature

in distinguishing between RGC and HGC

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The presence of mutational signatures

APOBEC signature mutation: TCW (where W = A or T)

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The APOBEC signature mutation

APOBEC signature mutation: TCW (where W = A or T)

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Mutational asymmetries in GC with WGS data

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Ultra-mutated

GC

Hyper-

mutatedGC

Regular-

mutatedGC

Mutational asymmetries in GC with WGS data

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Two types of mutational asymmetries

Transcription related

Replication related

NicholasJ.Haradhvalaetal.

Mutational asymmetries in GC with WGS data

24

NicholasJ.Haradhvalaetal.

Mutational asymmetries in GC with WGS data

25

NicholasJ.Haradhvalaetal.

Mutational asymmetries in GC with WGS data

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Asymmetry

plot

Regular-

mutatedGC

Hyper-

mutatedGC

Ultra-

mutatedGC

Principles to identify significantly

mutated genes

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adaptedfromTamboreraD.et al

Mutational landscape in regular-mutated GC

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PreviouslyunreportedSMGsincludes:

ITGAV,upstreamregulatorofPI3K,significantlydeletedin

HKandTCGAcohorts.

NEBA,focallydeletedintheHKcohort.

CNBD1,significantlymutatedinPan-Cancerstudy.

AKAP6,aproteinkinase,significantlymutatedinEAC.

…...

Altered signaling pathways in regular-mutated GC

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Mutational landscape in hyper-mutated GC

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Prognostic significance of C1/2 in RGC

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Prognosis of C1/2 stratified by

Lauren’s classification

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Prognostic significance of C1/2 in the 2

nd

cohort

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Prognosis of CDH1 mutation in

diffuse-/intestinal-type GC

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Prognosis of CDH1 mutation in

the 2

nd

diffuse-type GC cohort

35

Conclusions

1. There are ubiquitousandspecificmutationalprocesses

underlyingthepathogenesisofdifferentsubtypesofGC

withvaryingmutationburdens.

2. SeveralnovelSMGsthataremutatedatintermediateor

lowprevalencewereidentified.

3. Regular-mutated GC canbefurtherstratifiedintotwo

subtypes(i.e.C1/2)withdistinctclinicaloutcomes.

4. CDH1mutationisanindependentprognosticfactorfor

poorersurvivalinpatientswithdiffuse-typeGC.

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Publications

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1. Li, Xiangchun*, Wu,W. K.K.,Xing,R.,Wong,S.H.,&Liu,Yu, J. (2016). Distinct subtypes of gastric

cancer defined by molecular characterization include novel mutational signatures with prognostic

capability,CancerResearch76(7),1724–1733.doi:10.1158/0008-5472.CAN-15-2443

2. Nakatsu,G.,Li, Xiangchun*,Zhou,H.,Sheng,J.,Wong,S.H.,Wu,W.K.K.,…Yu, J., Sung,J.J.Y.(2015).

Gutmucosalmicrobiomeacrossstagesofcolorectalcarcinogenesis.Nature Communications,6,8727.

doi:10.1038/ncomms9727

3. Yu,J.,Wu,W.K.K.,Li, Xiangchun*,X.X.,He,J.,Li,X.-X.X.,Ng,S.S.M.,...Sung,J.J.Y.(2015).Novel

recurrentlymutatedgenesandaprognosticmutationsignatureincolorectalcancer.Gut,64(4),636–

45.doi:10.1136/gutjnl-2013-306620

4. Chen,K.,Yang,D.,Li, Xiangchun*,Sun,B.,Song,F.,Cao,W.,...Gao,Z.(2015).Mutationallandscapeof

gastric adenocarcinoma in Chinese : Implications for prognosis and therapy.Proceedings of the

National Academy of Sciences,6(1),1–6.doi:10.1073/pnas.1422640112

5. Song, Y., Li, L., Ou, Y., Gao, Z., Li, E.,Li, Xiangchun*, ... Zhan, Q. (2014). Identification of genomic

alterationsinoesophagealsquamouscellcancer.Nature,509(7498),91–5.doi:10.1038/nature13176

6. Song, F.,Li, Xiangchun*, Song, F., Zhao, Y., & Li, H. (2015). Comparative genomic analysis reveals

bilateralbreastcancersaregeneticallyindependent.Oncotarget.doi:10.18632/oncotarget.5569

7. Li,C.,Gao,Z.,Li,F.,Li, Xiangchun*,Sun,Y.,Wang,M.M.,...Wei,Q.(2015).WholeExomeSequencing

Identifies Frequent Somatic Mutations in Cell-Cell Adhesion Genes in Chinese Patients with Lung

SquamousCellCarcinoma.Scientific Reports,5(August),14237.doi:10.1038/srep14237

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8.Cao,Y.,He,M.,Gao,Z.,Peng,Y.,...Li, Xiangchun,...Ning,G.(2014).ActivatinghotspotL205RmutationinPRKACAand

adrenalCushing’ssyndrome.Science,344(6186),913–7.doi:10.1126/science.1249480 9.Zhang,L.,Zhou,Y.,Cheng,C.,Cui,

H.,Cheng,...Li, Xiangchun,...Cui,Y.(2015).Genomicanalysesrevealmutationalsignaturesandfrequentlyalteredgenesin

esophagealsquamouscellcarcinoma.American Journal of Human Genetics,96(4),597–611.doi:10.1016/j.ajhg.2015.02.017

10.Yu,C.,Yu,J.,Yao,X.,Wu,W.K.K.,Lu,Y.,...Li, Xiangchun,...Wang,J.J.(2014).Discoveryofbiclonaloriginandanovel

oncogene SLC12A5 in colon cancer by single-cell sequencing.Cell Research,24(6), 701–12. doi:10.1038/cr.2014.43 11.

Zhao,Y.,Yang,J.,Chen,Z.,Gao,Z.,Zhou,F.,Li, Xiangchun,...He,J.(2014).IdentificationofsomaticalterationsinstageI

lung adenocarcinomas by next- generation sequencing.Genes Chromosomes and Cancer,53(4), 289–298.

doi:10.1002/gcc.22138 12.Xu,L.,Li,X.X.,Cai,M.,Chen,J.,Li,X.X.,Wu,W.K.K.,...Li, Xiangchun ...Yu,J.(2015).Increased

expressionofSolutecarrierfamily12member5viageneamplificationcontributestotumourprogressionandmetastasis

andassociateswithpoorsurvivalincolorectalcancer.Gut,1–12.doi:10.1136/gutjnl-2014-308257

13.Liu,L.,Xu,Y.,He,M.,Zhang,M.,Cui,F.,Lu,L.,...Li, Xiangchun,...Esteban,M.A.(2014).Transcriptionalpausereleaseis

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... Cheng, A. S. L. (2016). Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates Nuclear

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16.Tang,S.,Wu,W.K.K.,Li, Xiangchun,Wong,S.H.,Wong,N.,Chan,M.T.V.,...Yu,J.(2016).StratificationofDigestive

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Acknowledgement

• Beijing Genomics Institute (BGI): Xiaodong Fang, Mengyao Wang,

Jiaqian Wang, Lin Li, Yong Zhou, Kunlong Qiu, Longyun Chen, ZhiBo

Gao, Jun He, Yingrui Li, Dr. Xiuqing Zhang, Dr. Jun Wang, Dr.

HuanmingYang

• The Chinese University of Hong Kong (CUHK): WilliamKKWu, Sunny

H.Wong, MatthewT.V.Chan, JosephJYSungand JunYu

• MD Anderson Cancer Center: Yuexin Liu and Wei Zhang

• TianjinMedicalUniversityCancerInstituteandHospital: Kexin Chen

• PekingUniversityCancerHospital&Institute: Rui Xing, Youyong Lu

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StateKeyLaboratoryofDigestiveDisease