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Background   KRAS  mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that  KRAS  codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with  KRAS  codon 61 or 146 mutation remain unclear.    Methods  We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined  KRAS  mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including  BRAF  and  PIK3CA  mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067  BRAF -wild-type cancers to avoid confounding by  BRAF  mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage,  PIK3CA  mutation, CIMP, LINE-1 hypomethylation, and MSI.    Results   KRAS  codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall  KRAS  mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to  KRAS -wild-type, overall,  KRAS -mutated cancers more frequently exhibited cecal location (24% vs. 12% in  KRAS -wild-type;  P  < 0.0001), CIMP-low (49% vs. 32% in  KRAS -wild-type;  P  < 0.0001), and  PIK3CA  mutations (24% vs. 11% in  KRAS -wild-type;  P  < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither  KRAS  codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].    Conclusions  Tumors with  KRAS  mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to  KRAS  codon 12 or 13 mutated cancers. To further assess clinical utility of  KRAS  codon 61 and 146 testing, large-scale trials are warranted.

molecular cancer

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review