title: KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study.
abstract: BACKGROUND
  Inhibitors of the epidermal growth factor (EGFR) signaling pathway have a major role in the treatment of KRAS wild-type colorectal cancer patients. The EGFR pathway has been shown to be activated in gastric cancer (GC). However, published data on KRAS and BRAF mutation status is limited in GC and has not been compared between GC from different geographic regions.
  
  
  METHODS
  The prevalence of KRAS and BRAF mutations was established in 712 GC: 278 GC from the United Kingdom, 230 GC from Japan and 204 GC from Singapore. The relationship between KRAS/BRAF mutation status, DNA mismatch repair (MMR) status, clinicopathological variables and overall survival was analysed.
  
  
  RESULTS
  Overall, 30 (4.2%) GC carried a KRAS mutation. In total, 5.8% of the UK GC, 4% of Japan GC and 1.5% of Singapore GC were KRAS mutant. KRAS mutant GC had fewer lymph node metastases in the UK cohort (P=0.005) and were more frequent in elderly patients in the Japan cohort (P=0.034). KRAS mutations were more frequent in MMR-deficient GC in the UK and the Japanese cohort (P<0.05). A BRAF mutation was only detected in a single Japanese GC.
  
  
  CONCLUSIONS
  This large multicentre study demonstrated that KRAS mutations and DNA MMR deficiency have a role in a small subgroup of GC irrespective of country of origin, suggesting that this subgroup of GC may have developed along a common pathway. Further studies need to establish whether concomitant mutations or amplifications of other EGFR signalling pathway genes may contribute to the activation of this pathway in GC.
authors.affiliation: Department of Pathology, VU University Medical Center, Po Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: N C T
authors.initials: NC
authors.lastname: van Grieken
authors.forename: T
authors.initials: T
authors.lastname: Aoyama
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authors.initials: T
authors.lastname: Aoyma
authors.forename: P A
authors.initials: PA
authors.lastname: Chambers
authors.forename: D
authors.initials: D
authors.lastname: Bottomley
authors.forename: L C
authors.initials: LC
authors.lastname: Ward
authors.forename: I
authors.initials: I
authors.lastname: Inam
authors.forename: T E
authors.initials: TE
authors.lastname: Buffart
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.forename: T
authors.initials: T
authors.lastname: Lim
authors.forename: B
authors.initials: B
authors.lastname: Pang
authors.forename: S L
authors.initials: SL
authors.lastname: Zhang
authors.forename: I B
authors.initials: IB
authors.lastname: Tan
authors.forename: B
authors.initials: B
authors.lastname: Carvalho
authors.forename: D A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Y
authors.initials: Y
authors.lastname: Kameda
authors.forename: T
authors.initials: T
authors.lastname: Arai
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.forename: A
authors.initials: A
authors.lastname: Tsuburaya
authors.forename: P
authors.initials: P
authors.lastname: Tan
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: H I
authors.initials: HI
authors.lastname: Grabsch
mesh_terms: D000368:Aged; D015331:Cohort Studies; D053843:DNA Mismatch Repair; D049914:DNA Repair-Deficiency Disorders; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins