Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study.
Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study.
复制标题
DOI：
10.1186/2042-6410-4-17
复制
发表时间：
2013-09-10
影响因子：
7.9
通讯作者：
Eberhard J
中科院分区：
文献类型：
--
作者：
Wangefjord S;Sundström M;Zendehrokh N;Lindquist KE;Nodin B;Jirström K;Eberhard J
激活KRAS和BRAF突变预测结直肠癌(CRC)对EGFR靶向治疗无反应，但它们的预后价值需要进一步验证。在这项研究中，我们在一项大型前瞻性队列研究中，总体上和按性别分层，调查了KRAS密码子12和13以及BRAF突变对结直肠癌患者生存率的影响。对马尔默饮食和癌症研究中525例和524例结直肠癌病例的肿瘤进行焦磷酸测序，分析了KRAS密码子12和13以及BRAF突变。对年龄、TNM分期、分化程度、血管侵犯和微卫星不稳定性(MSI)状态进行未校正和校正的Cox比例风险回归分析，探讨其与肿瘤特异性生存(CS)的关系。KRAS和BRAF突变是相互排斥的。525例患者中有191例(36.4%)存在KRAS突变，其中82.2%发生在第12位密码子，17.3%发生在第13位密码子，0.5%的患者两个密码子都有突变。BRAF基因突变78例(14.9%)。总体而言，KRAS密码子13的突变，而不是密码子12的突变，在未校正的分析中与显著降低的CS有关，但在校正分析中没有关联，并且BRAF突变对生存率没有显著影响。然而，在微卫星稳定(MSS)中，而不是在MSI肿瘤中，在未调整的分析中观察到BRAF突变对预后的不利影响，但在调整分析中没有观察到。虽然KRAS突变状态与性别无关，但BRAF突变在女性中更常见。在女性中，BRAF突变不能预测预后；但在男性中，在总体校正分析中，BRAF突变与显著降低的CS相关(HR=3.50；95%CI=1.41-8.70)，但在未校正分析中没有相关性。在男性MSS患者中，BRAF突变是预后不良的独立因素(HR=4.91；95%CI=1.99~12.12)。KRAS密码子13突变在女性中与显著降低的CS有关，但在未调整的男性中没有，但在调整后的分析中没有。这项队列研究的结果表明，在结直肠癌中，BRAF突变的预后价值与性别有关，在男性中尤为明显。这些发现是新颖的，值得进一步验证。
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. 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. 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. 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.