title: Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy.
abstract: OBJECTIVE
  Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs.
  
  
  METHODS
  We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed.
  
  
  RESULTS
  Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy.
  
  
  CONCLUSIONS
  Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ivanova
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.forename: Chee Wee
authors.initials: CW
authors.lastname: Ong
authors.forename: Niantao
authors.initials: N
authors.lastname: Deng
authors.forename: Julian
authors.initials: J
authors.lastname: Lee
authors.forename: Sze Huey
authors.initials: SH
authors.lastname: Tan
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Ming Hui
authors.initials: MH
authors.lastname: Lee
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Wai Keong
authors.initials: WK
authors.lastname: Wong
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuburaya
authors.forename: Heike
authors.initials: H
authors.lastname: Grabsch
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.forename: Steven
authors.initials: S
authors.lastname: Rozen
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Cheong
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Noh
authors.forename: Wei Kiat
authors.initials: WK
authors.lastname: Wan
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Manuel Salto
authors.initials: MS
authors.lastname: Tellez
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D037541:Galectin 4 / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C490584:CDH17 protein, human; D015820:Cadherins; D037541:Galectin 4; C511927:LGALS4 protein, human; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin; D005472:Fluorouracil