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

Molecular Cancer

Research

Yaoyu E Wang¹  Seungyoun Jung²  Andrew T Chan³  Mai Yamauchi⁴  Zhi Rong Qian⁴  Yu Imamura⁴  Xiaoyun Liao⁴  Jeffrey A Meyerhardt⁴  Shouyong Peng⁵  Adam J Bass⁵  Charles S Fuchs⁶  Aya Kuchiba⁷  Reiko Nishihara⁷  Shuji Ogino⁸  Paul Lochhead⁹  Kana Wu^1,10  Katsuhiko Nosho^1,11  Kevin M Haigis^1,12 

[1] Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA;Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Department of Nutrition, Harvard School of Public Health, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA;Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room M422, 02215, Boston, MA, USA;Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK;Department of Nutrition, Harvard School of Public Health, Boston, MA, USA;First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan;Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA;

关键词: Clinical outcome;    Colon cancer;    Genetic change;    RAF;    RAS;   

DOI  :  10.1186/1476-4598-13-135

 received in 2014-02-16, accepted in 2014-05-07,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundKRAS 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.MethodsWe 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.ResultsKRAS 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].ConclusionsTumors 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.

【 授权许可】

Unknown   
© Imamura et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.