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

Yu Imamura, Paul Lochhead, Mai Yamauchi, Aya Kuchiba, Zhi Rong Qian, Xiaoyun Liao, Reiko Nishihara, Seungyoun Jung, Kana Wu, Katsuhiko Nosho, Yaoyu E Wang, Shouyong Peng, Adam J Bass, Kevin M Haigis, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino

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Abstract

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.

Original languageEnglish
Article number135
JournalMolecular Cancer
Volume13
DOIs
Publication statusPublished - 31 May 2014

Bibliographical note

Acknowledgments
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 following state cancer registries for their help: AL, AZ, AR, CA, CO, CT,
DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH,
OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by U.S.
National Institute of Health (NIH) grants [P01 CA87969 to S.E. Hankinson; P01
CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to
CSF; R01 CA137178 to ATC; and R01 CA151993 to SO]; and by grants from
the Bennett Family Fund and the Entertainment Industry Foundation
through National Colorectal Cancer Research Alliance. ATC is a Damon
Runyon Clinical Investigator. PL is a Scottish Government Clinical Academic
Fellow and was supported by a Harvard University Frank Knox Memorial
Fellowship. The content is solely the responsibility of the authors and does
not necessarily represent the official views of NIH. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation
of the manuscript.

Keywords

  • clinical outcome
  • colon cancer
  • genetic change
  • RAF
  • RAS

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