title: Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.
abstract: OBJECTIVE
  Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents.
  
  
  METHODS
  We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening.
  
  
  RESULTS
  We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro.
  
  
  CONCLUSIONS
  Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer.
authors.affiliation: Centre for Computational Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Zhengdeng
authors.initials: Z
authors.lastname: Lei
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.forename: Kakoli
authors.initials: K
authors.lastname: Das
authors.forename: Niantao
authors.initials: N
authors.lastname: Deng
authors.forename: Hermioni
authors.initials: H
authors.lastname: Zouridis
authors.forename: Sharon
authors.initials: S
authors.lastname: Pattison
authors.forename: Clarinda
authors.initials: C
authors.lastname: Chua
authors.forename: Zhu
authors.initials: Z
authors.lastname: Feng
authors.forename: Yeoh Khay
authors.initials: YK
authors.lastname: Guan
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ivanova
authors.forename: Shenli
authors.initials: S
authors.lastname: Zhang
authors.forename: Minghui
authors.initials: M
authors.lastname: Lee
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Anna
authors.initials: A
authors.lastname: Ngo
authors.forename: Sravanthy
authors.initials: S
authors.lastname: Manesh
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tan
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Jimmy Bok Yan
authors.initials: JB
authors.lastname: So
authors.forename: Liang Kee
authors.initials: LK
authors.lastname: Goh
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.forename: Tony Kiat Hon
authors.initials: TK
authors.lastname: Lim
authors.forename: Horst
authors.initials: H
authors.lastname: Flotow
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005472:Fluorouracil / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012044:Regression Analysis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil
keywords: 5-FU; 5-fluorouracil; BFRM; Bayesian Factor Regression Modeling; CHC; CHC_IFS; CNA; CSC; Cancer Classification; DPD; FDR; GC-Class; GO; Gene Ontology; IFS; KEGG; Kyoto Encyclopedia of Genes and Genomes; PI3K; Personalized Cancer Treatment; SPEM; Stomach Cancer; TS; cancer stem cell; consensus hierarchical clustering; consensus hierarchical clustering with iterative feature selection; copy number alteration; dihydropyrimidine dehydrogenase; false discovery rate; gastric cancer classifier; iterative feature selection; mRNA; mTOR; mammalian target of rapamycin; messenger RNA; phosphatidylinositol 3-kinase; spasmolytic-polypeptide-expressing metaplasia; thymidylate synthase