<i>BRAF</i> and <i>NRAS</i> Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer.

Abstract

<b>Purpose:</b> Somatic mutation status at <i>KRAS, BRAF</i>, and <i>NRAS</i> 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.<b>Experimental Design:</b> We profiled 2,157 aCRCs for somatic mutations in <i>KRAS, BRAF</i>, and <i>NRAS</i> and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.<b>Results:</b><i>KRAS</i> 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; <i>P</i> = 6.4 × 10^-10 and HR, 1.53; 95% CI, 1.26-1.86; <i>P</i> = 1.5 × 10^-05, respectively]. For <i>BRAF,</i> more c.1781A>G (p.D594G) CRCs carried <i>RAS</i> mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178), <i>P</i> = 9.0 × 10^-03]. c.1799T>A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06-3.28; <i>P</i> = 1.0 × 10^-15), whereas c.1781A>G (p.D594G) was not (HR, 1.30; 95% CI, 0.73-2.31; <i>P</i> = 0.37); this intralocus difference was significant (<i>P</i> = 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), <i>P</i> = 3.7 × 10^-03]. For <i>NRAS</i>, 5% (3/60) of codon 61 mutant colorectal cancers had <i>KRAS</i> mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (<i>P</i> = 7.9 × 10^-05). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09-1.99; <i>P</i> = 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64-2.58; <i>P</i> = 0.48).<b>Conclusions:</b> Our data show considerable intralocus variation in the outcomes of mutations in <i>BRAF</i> and <i>NRAS</i> These data need to be considered in patient management and personalized cancer therapy. <i>Clin Cancer Res; 23(11); 2742-9. ©2016 AACR</i>.