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

Abstract

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. .

Clinical Features and Outcomes of Patients with Colorectal Cancers Harboring NRAS Mutations

“…A recent pooled analysis of five randomized trials in mCRC that included 39 patients with NRAS mutant tumors, however, did not find a significant effect of NRAS mutation status on survival(24). An analysis of NRAS mutation locus by Summers et al (25) suggests that prognostic effects of NRAS mutation in mCRC vary by mutation locus with no clear effect for exon 2 mutants, but shorter survival for codon 61 mutants. Consistent with this study, we find that exon 3 NRAS mutants are associated with a strong effect on survival (hazard ratio of 2.85 versus RAS mutant tumors and of 2.0 versus NRAS exon 2 mutant tumors) and find no significant effect for exon 2 NRAS mutants compared to RAS wild-type tumors.…”

Colon cancer with micropapillary carcinoma component: a clinopathologic study of 9 cases

“…In contrast, micropapillary carcinoma does not seem to be involved in epithelial-mesenchymal transition, based on the results of this study. The alteration of BRAF or ALK gene has been identified in colon cancer [24,25,26]. However, these genes do not seem to be involved in the pathogenesis of colon micropapillary carcinoma.…”

Cancer modeling in colorectal organoids reveals intrinsic differences between oncogenic RAS and BRAF variants

“…Despite the overlapping functions of RAS and BRAF oncogenes, data analyses of CRC patients and cell lines suggest that mutation variants of oncogenic RAS and BRAF proteins are associated with different tumor types and involved in distinct tumorigenic pathways 17,23,61,62 . Moreover, CRCs with oncogenic RAS variants can react differently to pan-HER inhibition [20][21][22]63,64 .…”

“…In particular, intrinsic differences in tumorigenic potential between mutant variants is challenging to dissect, considering the immense different mutational backgrounds per human tumor 5 . Moreover, NRAS mutations are more often detected in tumors of the left colon, whereas KRAS mutant tumors are most frequently found in right colon 14,23 , creating the possibility that these are two different tumor subtypes of different epigenetic make-up and cellular composition. The situation is even more extreme for oncogenic mutations in BRAF (mostly V600E) that are detected in approximately 11% of CRC cases 4 .…”

“…The situation is even more extreme for oncogenic mutations in BRAF (mostly V600E) that are detected in approximately 11% of CRC cases 4 . In contrast to RAS mutations, BRAF mutations are common in tumors with a hypermutation phenotype (microsatellite unstable) 24 , show co-occurrence with WNT pathway mutations in RNF43 rather than in APC 4,5 and show different metastatic behavior 16,23 . To optimize personalized cancer treatment of CRC patients, we set out to improve our understanding of genotype-phenotype correlations and investigate the intrinsic similarities and differences between a series of common mutations in the EGFR signaling pathway.…”