Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study

Biology of Sex Differences

Sakarias Wangefjord²  Magnus Sundström³  Nooreldin Zendehrokh²  Kajsa Ericson Lindquist²  Björn Nodin²  Karin Jirström²  Jakob Eberhard¹ 

[1] Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden

[2] Department of Clinical Sciences, Division of Pathology, Lund University, Lund, Sweden

[3] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

关键词: Prognosis;    Sex;    Colorectal cancer;    BRAF mutation;    Codon 13;    Codon 12;    KRAS mutation;   

Others  :  793018
DOI  :  10.1186/2042-6410-4-17

 received in 2013-08-13, accepted in 2013-08-30,  发布年份 2013

【 摘 要 】

Background

Activating KRAS and BRAF mutations predict unresponsiveness to EGFR-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation. In this study, we investigated the impact of KRAS codons 12 and 13, and BRAF mutations on survival from CRC, overall and stratified by sex, in a large prospective cohort study.

Methods

KRAS codons 12 and 13, and BRAF mutations were analysed by pyrosequencing of tumours from 525 and 524 incident CRC cases in The Malmö Diet and Cancer Study. Associations with cancer-specific survival (CSS) were explored by Cox proportional hazards regression, unadjusted and adjusted for age, TNM stage, differentiation grade, vascular invasion and microsatellite instability (MSI) status.

Results

KRAS and BRAF mutations were mutually exclusive. KRAS mutations were found in 191/ 525 (36.4%) cases, 82.2% of these mutations were in codon 12, 17.3% were in codon 13, and 0.5% cases had mutations in both codons. BRAF mutations were found in 78/524 (14.9%) cases. Overall, mutation in KRAS codon 13, but not codon 12, was associated with a significantly reduced CSS in unadjusted, but not in adjusted analysis, and BRAF mutation did not significantly affect survival. However, in microsatellite stable (MSS), but not in MSI tumours, an adverse prognostic impact of BRAF mutation was observed in unadjusted, but not in adjusted analysis. While KRAS mutation status was not significantly associated with sex, BRAF mutations were more common in women. BRAF mutation was not prognostic in women; but in men, BRAF mutation was associated with a significantly reduced CSS in overall adjusted analysis (HR = 3.50; 95% CI = 1.41–8.70), but not in unadjusted analysis. In men with MSS tumours, BRAF mutation was an independent factor of poor prognosis (HR = 4.91; 95% CI = 1.99–12.12). KRAS codon 13 mutation was associated with a significantly reduced CSS in women, but not in men in unadjusted, but not in adjusted analysis.

Conclusions

Results from this cohort study demonstrate sex-related differences in the prognostic value of BRAF mutations in colorectal cancer, being particularly evident in men. These findings are novel and merit further validation.

【 授权许可】

   
2013 Wangefjord et al.; licensee BioMed Central Ltd.

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