KRAS mutations worsen overall survival (OS) in Black but not White colon cancer patients

Background . Disparities between Black (BA) and White Americans (WA) exist for incidence and OS among colon cancer (CC) patients. Identifying race-associated markers for OS may elicit CC treatment approaches to improve OS. We previously demonstrated that low-levels of microsatellite instability (MSI-L) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are associated with shorter CC recurrence-free survival. We also showed that MSI-L/EMAST with loss of heterozygosity (LOH) at chromosome 9p21-24 (9p-LOH) improves OS of CC patients. Additionally, we and others have observed high prevalence of KRAS and BRAF mutations in BA and WA CCs, respectively. Here, we examined race-associated differences in KRAS and BRAF mutations, 9p-LOH, and MSI-L/EMAST, and examined their prognostic values. Methods . Three hundred-fifty CC cases (175 WA and 175 BA) from the North Carolina Colon Cancer Study were analyzed for associations between race and genetic alterations. Chromosome 9p-LOH was determined at 4 single nucleotide polymorphism (SNP) loci present on 9p21-24 by digital PCR. MSI-L/ EMAST was determined from 14 microsatellite markers, including 2 mono-, 5 di-, and 7 tetra-nucleotide markers by fragment analysis. KRAS G12/13 and BRAF V600E mutations were determined by Sanger sequencing of PCR products generated from targeted regions. Results . Among the 175 BA CC cases, 82 (46.8%) had KRAS mutations compared to 31.1% (53/169) of WA cases (O.R.: 1.97, 95%CI: 1.27-3.06, P =0.002). More WA CC cases (10.9%: 19/156) exhibited BRAF mutations than BA CC (6.1%: 10/165) but this difference did not reach significance ( P =0.075). There was no association between MSI-L/EMAST and race ( P =0.5). Chromosome 9p-LOH was detected in 15.2% of BA CC cases (19/125) and 9p-LOH with MSI-L/EMAST was detected in 8.6% of BA cases (12/140). Chromosome 9p-LOH prevalence was higher among WA CC vs BA CC in our initial subset analysis of 42 patients. Among BA CC cases, KRAS mutations were associated with shorter 5yr OS (H.R.: 1.91, 95%CI: 1.11-3.29, P =0.018) and 10yr OS (H.R.: 1.55, 95%CI: 1.02-2.37, P =0.04), and when adjusted for MSI-L/EMAST, tumor stage/location, and smoking status, KRAS mutations were associated with shorter 5yr OS (H.R.: 2.20, 95%CI: 1.27-3.8), P =0.0045) and 10yr OS (H.R.: 1.8, 95%CI: 1.17-2.78: P =0.0075). Among WA CC cases, there was no association between KRAS mutations and either 5yr OS ( P =0.85) or 10yr OS ( P =0.82). Conclusion s. KRAS G12/13 mutations are more frequent in BA CC than WA CC and are a poor prognostic factor for BA CC OS. The significance of 9p-LOH and 9p-LOH plus MSI-L/EMAST in WA CC is being currently assessed.