Microsatellite Instability and BRAF Mutation Testing in Colorectal Cancer Prognostication

J Natl Cancer Inst. 2013 Aug 7;105(15):1151-6. doi: 10.1093/jnci/djt173. Epub 2013 Jul 22.

Abstract

BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • CpG Islands*
  • DNA Methylation*
  • DNA Mutational Analysis
  • Female
  • Humans
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Mutation*
  • Odds Ratio
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*

Substances

  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf