title: Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.
abstract: Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Razvan
authors.initials: R
authors.lastname: Cristescu
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nebozhyn
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Ting
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Swee Seong
authors.initials: SS
authors.lastname: Wong
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Yong Gang
authors.identifier: 0000000237600718
authors.initials: YG
authors.lastname: Yue
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Xiang S
authors.initials: XS
authors.lastname: Ye
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.affiliation: BGI Tech Solutions, Hong Kong, China.
authors.forename: Shawn
authors.initials: S
authors.lastname: Liu
authors.affiliation: BGI Tech Solutions, Hong Kong, China.
authors.forename: Lara
authors.initials: L
authors.lastname: Gong
authors.affiliation: Shanghai Biocorp, Shanghai, China.
authors.forename: Jake
authors.initials: J
authors.lastname: Fu
authors.affiliation: Shanghai Biocorp, Shanghai, China.
authors.forename: Jason Gang
authors.initials: JG
authors.lastname: Jin
authors.affiliation: Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Min Gew
authors.initials: MG
authors.lastname: Choi
authors.affiliation: Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Sohn
authors.affiliation: Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Bae
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Biostatistics and Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Insuk
authors.initials: I
authors.lastname: Sohn
authors.affiliation: Biostatistics and Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sin-Ho
authors.initials: SH
authors.lastname: Jung
authors.affiliation: 1] Program in Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [2] Genome Institute of Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hardwick
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kang
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ayers
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Hongyue
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhard
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research Laboratories, Merck Sharpe &Dohme, Boston, Massachusetts, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Lilly Research Labs, Eli Lilly &Co, Indianapolis, Indiana, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Aggarwal
mesh_terms: D000368:Aged; D015331:Cohort Studies; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D013274:Stomach Neoplasms / Q000235:genetics* / Q000628:therapy; D046888:Tissue Array Analysis; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53