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 to 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: Utilizing molecular pathological epidemiology database of 1261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1075 BRAF-wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation.RESULTS: Compared to 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 greater than 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 to KRAS-wild-type/BRAF-wild-type cases. CONCLUSIONS: KRAS codon 12 mutations (in particular, c.35G greater than 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.
Bibliographical notePMID: 22753589 [PubMed - indexed for MEDLINE] PMCID: PMC3624899 Free PMC Article
This work was supported by the National Institute of Health [P01 CA87969 (to S.E. Hankinson), P01 CA55075 (to W.C. Willett), P50 CA127003 (to C.S.F.), and R01 CA151993 (to S.O.)]; the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. TM was supported by a fellowship grant from the Japan Society for Promotion of Science. PL was supported by Frank Knox Memorial Fellowship from Harvard University. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript.
We deeply thank hospitals and pathology departments throughout the U.S. for generously providing us with tissue specimens. In addition, we would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the U.S. state cancer registries for their help.