title: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.
abstract: Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.
authors.affiliation: 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2].
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2].
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
authors.affiliation: 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2] [3].
authors.forename: Jiangchun
authors.initials: J
authors.lastname: Xu
authors.affiliation: 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2].
authors.forename: Siu Po
authors.initials: SP
authors.lastname: Lee
authors.affiliation: 1] Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. [2].
authors.forename: Helen H N
authors.initials: HH
authors.lastname: Yan
authors.affiliation: External Research Solutions, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Shi
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Hoi Cheong
authors.initials: HC
authors.lastname: Siu
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Shibing
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Kent Man
authors.initials: KM
authors.lastname: Chu
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Simon
authors.initials: S
authors.lastname: Law
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Kok Hoe
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Annie S Y
authors.initials: AS
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Wai Yin
authors.initials: WY
authors.lastname: Tsui
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Siu Lun
authors.initials: SL
authors.lastname: Ho
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Anthony K W
authors.initials: AK
authors.lastname: Chan
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Jonathan L K
authors.initials: JL
authors.lastname: Man
authors.affiliation: Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Foglizzo
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Man Kin
authors.initials: MK
authors.lastname: Ng
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: April S
authors.initials: AS
authors.lastname: Chan
authors.affiliation: Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yick Pang
authors.identifier: 0000000264618358
authors.initials: YP
authors.lastname: Ching
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Grace H W
authors.initials: GH
authors.lastname: Cheng
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Fernandez
authors.affiliation: Division of Stem Cell Biology and Developmental Genetics, Medical Research Council (MRC) National Institute for Medical Research, London, UK.
authors.forename: Vivian S W
authors.initials: VS
authors.lastname: Li
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.affiliation: 1] Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California, USA. [2].
authors.forename: Mao
authors.identifier: 0000000285708571
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
mesh_terms: D022005:Adherens Junctions; D000465:Algorithms; D000818:Animals; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D015894:Genome, Human; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics
chemical_list: C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein