Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers

Abstract

Purpose: To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared with codon 13 mutations, we hypothesized that KRAS codon 12-mutated colorectal cancers might behave more aggressively than KRAS wild-type tumors and codon 13 mutants.

Experimental design: Using molecular pathological epidemiology database of 1,261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1,075 BRAF wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality HR, adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation.

Results: Compared with patients with KRAS wild-type/BRAF wild-type cancers (N = 635), those with KRAS codon 12 mutations (N = 332) experienced significantly higher colorectal cancer-specific mortality [log-rank P = 0.0001; multivariate HR, 1.30; 95% confidence interval (CI), 1.02-1.67; P = 0.037], whereas KRAS codon 13-mutated cases (N = 108) were not significantly associated with prognosis. Among the seven most common KRAS mutations, c.35G>T (p.G12V; N = 93) was associated with significantly higher colorectal cancer-specific mortality (log-rank P = 0.0007; multivariate HR, 2.00; 95% CI, 1.38-2.90, P = 0.0003) compared with KRAS wild-type/BRAF wild-type cases.

Conclusions: KRAS codon 12 mutations (in particular, c.35G>T), but not codon 13 mutations, are associated with inferior survival in BRAF wild-type colorectal cancer. Our data highlight the importance of accurate molecular characterization in colorectal cancer.

Figure 1

Flow chart of the current study. BRAF-mutated cases (N=181) were excluded from survival analysis to assess a prognostic role of KRAS mutation in BRAF-wild-type tumors. In addition, cases with KRAS mutations in both codons 12 and 13 (N=5) were excluded, in order to assess a prognostic effect of KRAS codon 12 mutations separately from that of KRAS codon 13 mutations.

Figure 2

Kaplan-Meier curves of BRAF-wild-type colorectal cancer patients according to KRAS mutation status. KRAS-mutated BRAF-wild-type cases were compared to KRAS-wild-type/BRAF-wild-type cases to assess a prognostic role of KRAS mutation independent of BRAF mutation status. Table indicates the number of patients who were alive and at risk of death at each time point after diagnosis of colorectal cancer. (A) Colorectal cancer-specific survival according to KRAS codon 12 or 13 mutation status. (B) Overall survival according to KRAS codon 12 or 13 mutation status. (C) Colorectal cancer-specific survival according to KRAS c.35G>T (p.G12V) or c.34G>C (p.G12R) mutation status. (D) Overall survival according to KRAS c.35G>T (p.G12V) or c.34G>C (p.G12R) mutation status.

Figure 2

Kaplan-Meier curves of BRAF-wild-type colorectal cancer patients according to KRAS mutation status. KRAS-mutated BRAF-wild-type cases were compared to KRAS-wild-type/BRAF-wild-type cases to assess a prognostic role of KRAS mutation independent of BRAF mutation status. Table indicates the number of patients who were alive and at risk of death at each time point after diagnosis of colorectal cancer. (A) Colorectal cancer-specific survival according to KRAS codon 12 or 13 mutation status. (B) Overall survival according to KRAS codon 12 or 13 mutation status. (C) Colorectal cancer-specific survival according to KRAS c.35G>T (p.G12V) or c.34G>C (p.G12R) mutation status. (D) Overall survival according to KRAS c.35G>T (p.G12V) or c.34G>C (p.G12R) mutation status.