结直肠癌中的 BRAF 突变与独特的临床特征和较差的预后相关。

BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis.

机构信息

Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

出版信息

Dis Colon Rectum. 2012 Feb;55(2):128-33. doi: 10.1097/DCR.0b013e31823c08b3.

DOI:10.1097/DCR.0b013e31823c08b3

PMID:22228154

Abstract

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, χ 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.

摘要

背景

结直肠癌是一种具有多种潜在遗传突变的异质性疾病，这些突变导致不同的临床表型。BRAF 癌基因的突变是甲基化途径向结直肠癌恶性转化的关键步骤。然而，关于 BRAF 突变结直肠肿瘤的信息很少。

目的

本研究定义了与结直肠癌 BRAF 突变相关的临床特征和肿瘤学结局。

设计

研究了来自单一机构冷冻肿瘤生物库的结直肠腺癌。分离基因组 DNA，通过聚合酶链反应扩增并直接测序分析 BRAF 癌基因的突变。如果测试的任何一个位点发生突变，则将样本分类为突变型。记录患者和肿瘤特征，包括患者年龄、性别、肿瘤位置、肿瘤分化和微卫星不稳定性。

主要观察指标

通过 Fisher 确切概率检验、卡方检验或 Wilcoxon 分析确定与 BRAF 突变肿瘤的统计学关联。Kaplan-Meier 估计和多变量 Cox 回归分析用于总生存。

结果

共纳入 475 例结直肠腺癌患者，56 例样本存在 BRAF 突变（12%）。BRAF 野生型和突变型肿瘤在年龄（66 岁 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）和微卫星不稳定频率（16% vs 76%，p < 0.001）方面存在显著差异。BRAF 突变型和野生型人群的癌症分期无差异。对 322 例 I 期至 III 期疾病患者进行生存数据分析，BRAF 突变患者的总生存时间短于无突变患者（p = 0.018）。使用 Cox 回归分析，BRAF 突变独立于微卫星不稳定状态，与较差的总生存相关（HR 1.79，CI 1.05-3.05，p = 0.03）。