Microsatellite Instability and BRAF Mutation Testing in Colorectal Cancer Prognostication
Microsatellite Instability and BRAF Mutation Testing in Colorectal Cancer Prognostication
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DOI：
10.1093/jnci/djt173
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发表时间：
2013-08-01
影响因子：
10.3
通讯作者：
Ogino, Shuji
中科院分区：
文献类型：
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作者：
Lochhead, Paul;Kuchiba, Aya;Ogino, Shuji
结直肠癌中的 BRAF 突变通过其与高水平 CpG 岛甲基化表型 (CIMP) 和 MLH1 启动子甲基化的关系而与微卫星不稳定性 (MSI) 相关。 MSI 和 BRAF 突变分析通常用于家族癌症风险评估。为了阐明 MSI/BRAF 亚组组合的临床结果关联，我们调查了护士健康研究和健康专业人员随访研究中 1253 名直肠癌和结肠癌患者的生存率，并利用了临床和其他分子特征的可用数据，包括 CIMP、LINE-1 低甲基化以及 KRAS 和 PIK3CA 突变。与大多数微卫星稳定 (MSS)/BRAF 野生型、MSS/BRAF 突变型、MSI 高/BRAF 突变型和 MSI 高/BRAF 野生型亚型相比，多变量结直肠癌特异性死亡率风险比为 1.60（95% 置信区间 [CI] 1.12 至 2.28；P < .009）， 分别为 0.48（95% CI 0.27 至 0.87；P < .02）和 0.25（95% CI 0.12 至 0.52；P < .001）。没有证据表明 MSI 状态对 BRAF 突变具有不同的预后作用（P 交互作用 > .50）。结直肠癌的组合 BRAF/MSI 状态是用于预后风险分层的肿瘤分子生物标志物。
BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAFwild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAFwild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] 1.12 to 2.28; P .009), 0.48 (95% CI 0.27 to 0.87; P .02), and 0.25 (95% CI 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P-interaction > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.