BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer

Somatic mutation status at , and is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters. We profiled 2,157 aCRCs for somatic mutations in , and and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology. mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.61; = 6.4 × 10 and HR, 1.53; 95% CI, 1.26-1.86; = 1.5 × 10 , respectively]. For more c.1781A>G (p.D594G) CRCs carried mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178), = 9.0 × 10 ]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28; = 1.0 × 10 ), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31; = 0.37); this intralocus difference was significant ( = 0.04). More c.1799T>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>G (p.D594G) colorectal cancers [7% (1/15), = 3.7 × 10 ]. For , 5% (3/60) of codon 61 mutant colorectal cancers had mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers ( = 7.9 × 10 ). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99; = 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58; = 0.48). Our data show considerable intralocus variation in the outcomes of mutations in and These data need to be considered in patient management and personalized cancer therapy. .