title: Molecular classification of gastric cancer: a new paradigm.
abstract: OBJECTIVE
  Gastric cancer may be subdivided into 3 distinct subtypes--proximal, diffuse, and distal gastric cancer--based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology. Our aim is to test the hypothesis that these distinct gastric cancer subtypes may also be distinguished by gene expression analysis.
  
  
  METHODS
  Patients with localized gastric adenocarcinoma being screened for a phase II preoperative clinical trial (National Cancer Institute, NCI #5917) underwent endoscopic biopsy for fresh tumor procurement. Four to 6 targeted biopsies of the primary tumor were obtained. Macrodissection was carried out to ensure more than 80% carcinoma in the sample. HG-U133A GeneChip (Affymetrix) was used for cDNA expression analysis, and all arrays were processed and analyzed using the Bioconductor R-package.
  
  
  RESULTS
  Between November 2003 and January 2006, 57 patients were screened to identify 36 patients with localized gastric cancer who had adequate RNA for expression analysis. Using supervised analysis, we built a classifier to distinguish the 3 gastric cancer subtypes, successfully classifying each into tightly grouped clusters. Leave-one-out cross-validation error was 0.14, suggesting that more than 85% of samples were classified correctly. Gene set analysis with the false discovery rate set at 0.25 identified several pathways that were differentially regulated when comparing each gastric cancer subtype to adjacent normal stomach.
  
  
  CONCLUSIONS
  Subtypes of gastric cancer that have epidemiologic and histologic distinctions are also distinguished by gene expression data. These preliminary data suggest a new classification of gastric cancer with implications for improving our understanding of disease biology and identification of unique molecular drivers for each gastric cancer subtype.
authors.affiliation: Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.forename: Laura
authors.initials: L
authors.lastname: Tang
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Hans
authors.initials: H
authors.lastname: Gerdes
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000145:classification / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009367:Neoplasm Staging / Q000379:methods; D013274:Stomach Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor