Clinicopathological, molecular, and prognostic features of colorectal carcinomas with KRAS c.34G>T (p.G12C) mutation

Abstract Evidence indicates that combinations of anti‐EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)‐low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS ‐wild‐type tumors (31%). KRAS c.34G>T mutants showed higher CIMP‐high prevalence (14%) and lower CIMP‐negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T‐mutated tumors were associated with cecal location, non‐microsatellite instability (MSI)‐high status, BRAF wild type, and PIK3CA mutation when compared with KRAS ‐wild‐type tumors. Compared with BRAF ‐mutated tumors, KRAS c.34G>T mutants showed more frequent LINE‐1 hypomethylation, a biomarker for early‐onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum ( F. animalis ), pks + Escherichia coli , Bifidobacterium , or (enterotoxigenic) Bacteroides fragilis . Among 1122 BRAF ‐wild‐type colorectal carcinomas, compared with KRAS ‐wild‐type tumors, multivariable‐adjusted colorectal cancer‐specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05–3.17) in KRAS c.34G>T (p.G12C)‐mutated tumors ( p = 0.035) and 1.57 (1.22–2.02) in other KRAS ‐mutated tumors ( p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma.