BRAF Mutations in Colorectal Cancer Are Associated With Distinct Clinical Characteristics and Worse Prognosis
BRAF Mutations in Colorectal Cancer Are Associated With Distinct Clinical Characteristics and Worse Prognosis
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DOI：
10.1097/dcr.0b013e31823c08b3
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Church, James M.
中科院分区：
文献类型：
--
作者：
Kalady, Matthew F.;DeJulius, Kathryn L.;Church, James M.
背景：结直肠癌是一种异质性疾病，具有多种潜在的基因突变，导致不同的临床表型。BRAF癌基因突变是结直肠癌甲基化途径中恶性转化的关键步骤。然而，有一个缺乏的信息BRAF突变大肠tumors.OBJECTIVE：这项研究定义的临床特征和肿瘤学结果与大肠癌BRAF突变。设计：大肠腺癌从一个单一的机构冷冻肿瘤生物库进行了研究。分离基因组DNA，通过聚合酶链反应扩增，然后直接测序，分析BRAF癌基因中的突变。如果任何测试的基因座突变，则将样品分类为突变体。患者和肿瘤的特征，包括患者的年龄，性别，肿瘤的位置，肿瘤分化，和微卫星stability.Main结局measurements：统计学与BRAF突变肿瘤的关系，通过Fisher精确概率检验，卡方检验，或Wilcoxon分析。Kaplan-Meier估计和多变量考克斯回归分析进行了总survival.RESULTS：四百七十五结直肠腺癌纳入研究人群，56例样本窝藏BRAF突变（12%）。BRAF野生型和突变型肿瘤在年龄（66 vs 75岁，p = 0.004）、女性（44% vs 71%，p < 0.001）、近端肿瘤位置（44% vs 95%，p < 0.001）和微卫星不稳定性频率（16% vs 76%，p < 0.001）方面存在显著差异。BRAF突变体和野生型人群之间的癌症分期没有差异。对322例I期至III期患者的生存数据进行了分析，BRAF突变患者的总生存率低于无突变患者（p = 0.018）。考克斯回归分析显示，BRAF基因突变与微卫星不稳定状态无关，BRAF基因突变使总生存率降低（HR 1.79，CI 1.05-3.05，p = 0.03）。
BACKGROUND: Colorectal cancer is a heterogeneous disease with multiple underlying genetic mutations causing different clinical phenotypes. Mutation in the BRAF oncogene is a key step in malignant transformation within the methylator pathway to colorectal cancer. However, there is a paucity of information about BRAF mutant colorectal tumors.OBJECTIVE: This study defines the clinical characteristics and oncologic outcome associated with colorectal cancer BRAF mutations.DESIGN: Colorectal adenocarcinomas from a single-institution frozen-tumor biobank were studied. Genomic DNA was isolated and analyzed for mutations in the BRAF oncogene by polymerase chain reaction amplification followed by direct sequencing. A sample was classified as mutant if any of the tested loci were mutated. Patient and tumor characteristics were recorded including patient age, sex, tumor location, tumor differentiation, and microsatellite instability.MAIN OUTCOME MEASURES: Statistical associations with BRAF mutant tumors were determined by the Fisher exact probability test, chi(2) test, or Wilcoxon analysis. Kaplan-Meier estimates and multivariate Cox regression analysis were performed for overall survival.RESULTS: Four hundred seventy-five colorectal adenocarcinomas were included in the study population; 56 samples harbored a BRAF mutation (12%). There were significant differences between BRAF wild-type and mutant tumors in age (66 vs 75 years, p = 0.004), female sex (44% vs 71%, p < 0.001), proximal tumor location (44% vs 95%, p < 0.001), and frequency of microsatellite instability (16% vs 76%, p < 0.001). There was no difference in cancer stage between BRAF mutant and wild-type populations. Survival data were analyzed for 322 patients with stage I to III disease, and patients with a BRAF mutation had decreased overall survival than those without a mutation (p = 0.018). With the use of Cox regression analysis, BRAF mutation conferred a worse overall survival (HR 1.79, CI 1.05-3.05, p = 0.03) independent of microsatellite instability status.CONCLUSIONS: BRAF mutations in colorectal cancers are associated with distinct clinical characteristics and worse prognosis.