title: Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers.
abstract: OBJECTIVE
  To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared with codon 13 mutations, we hypothesized that KRAS codon 12-mutated colorectal cancers might behave more aggressively than KRAS wild-type tumors and codon 13 mutants.
  
  
  METHODS
  Using molecular pathological epidemiology database of 1,261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1,075 BRAF wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality HR, adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation.
  
  
  RESULTS
  Compared with patients with KRAS wild-type/BRAF wild-type cancers (N = 635), those with KRAS codon 12 mutations (N = 332) experienced significantly higher colorectal cancer-specific mortality [log-rank P = 0.0001; multivariate HR, 1.30; 95% confidence interval (CI), 1.02-1.67; P = 0.037], whereas KRAS codon 13-mutated cases (N = 108) were not significantly associated with prognosis. Among the seven most common KRAS mutations, c.35G>T (p.G12V; N = 93) was associated with significantly higher colorectal cancer-specific mortality (log-rank P = 0.0007; multivariate HR, 2.00; 95% CI, 1.38-2.90, P = 0.0003) compared with KRAS wild-type/BRAF wild-type cases.
  
  
  CONCLUSIONS
  KRAS codon 12 mutations (in particular, c.35G>T), but not codon 13 mutations, are associated with inferior survival in BRAF wild-type colorectal cancer. Our data highlight the importance of accurate molecular characterization in colorectal cancer.
authors: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave., Room JF-215C, Boston, MA 02215, USA.
authors: Yu
authors: Y
authors: Imamura
authors: Teppei
authors: T
authors: Morikawa
authors: Xiaoyun
authors: X
authors: Liao
authors: Paul
authors: P
authors: Lochhead
authors: Aya
authors: A
authors: Kuchiba
authors: Mai
authors: M
authors: Yamauchi
authors: Zhi Rong
authors: ZR
authors: Qian
authors: Reiko
authors: R
authors: Nishihara
authors: Jeffrey A
authors: JA
authors: Meyerhardt
authors: Kevin M
authors: KM
authors: Haigis
authors: Charles S
authors: CS
authors: Fuchs
authors: Shuji
authors: S
authors: Ogino
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D053208:Kaplan-Meier Estimate; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D053842:Microsatellite Instability; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins