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. .

No abstract

Background Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. Methods We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. Results Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40). Conclusion In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. Experimental design: For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COINeB (oxaliplatin and fluoropyrimidine chemotherapy AE cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P Z 6.6 Â 10 À4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. Results: Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21 e1.71, P Z 5.0 Â 10 À5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple

<p>Figure - Correlation plot showing inter- and intra-genic relationships between somatic KRAS, BRAF and NRAS mutations and MSI status in aCRC. Tables - Heterogeneity Tests comparing OS to diagnosis to death (Table S1) and the effect of cetuximab on OS (Table S2).</p>