Poor Survival Associated with the BRAF V600E Mutation in Microsatellite-Stable Colon Cancers

Abstract

The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large populationbased sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatelliteunstable tumors. (Cancer Res 2005; 65(14): 6063-9)

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

“…Several studies have shown that BRAF V600E mutation does not affect prognosis in colorectal cancers with high-level microsatellite instability, but adversely affects survival in microsatellitestable colorectal cancers. [31][32][33][34] This phenomenon was also observed in signet ring cell carcinoma in this series with 43% 5-year survival in microsatellitestable cases lacking BRAF V600E mutation compared with none among tumors with the mutation.…”

“…BRAF V600E mutation occurs in 34-80% of cancers with high level of microsatellite instability and 5-15% of microsatellite-stable cancers. [31][32][33][34] BRAF V600E mutation has been associated with poor survival in patients with microsatellite-stable, but not microsatellite-unstable, colorectal cancers. [31][32][33][34] In fact, BRAF V600E mutation does not adversely affect the favorable survival associated with tumors that show high level of microsatellite instability.…”

“…[31][32][33][34] BRAF V600E mutation has been associated with poor survival in patients with microsatellite-stable, but not microsatellite-unstable, colorectal cancers. [31][32][33][34] In fact, BRAF V600E mutation does not adversely affect the favorable survival associated with tumors that show high level of microsatellite instability. 31 Although genetic and epigenetic changes in colorectal cancer have been extensively studied, there are sparse data on the molecular features of signet ring cell carcinoma.…”

“…[31][32][33][34] In fact, BRAF V600E mutation does not adversely affect the favorable survival associated with tumors that show high level of microsatellite instability. 31 Although genetic and epigenetic changes in colorectal cancer have been extensively studied, there are sparse data on the molecular features of signet ring cell carcinoma. 15,35 The relationship of molecular changes and survival in signet ring cell carcinoma remains unclear.…”

ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics

“…Furthermore, the presence of B-raf mutations in colorectal cancer is estimated to be about 10% of unselected colorectal cancers [42-44]. In particular, B-raf T1799A mutation (V600E) has been reported in 4% of microsatellite stable (MSS) tumors whereas in microsatellite unstable tumors the percentage rises up to 27-52% [42,44-46]. By analogy to those investigations we detected V600E B-raf mutations in about 7% of MSS tumors and in 21% of MSI unstable tumors.…”