A prospective, multicenter, population-based study of BRAF mutational analysis for lynch syndrome screening
A prospective, multicenter, population-based study of BRAF mutational analysis for lynch syndrome screening
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DOI：
10.1016/j.cgh.2007.10.011
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发表时间：
2008-02-01
影响因子：
12.6
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中科院分区：
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背景与目的：错配修复(MMR)缺陷是Lynch综合征肿瘤的特征，然而，在大约15%的散发性结直肠癌(CRC)中，这些缺陷最常与MMR基因MLH1的体细胞甲基化有关。最近，由于MLH1启动子甲基化，BRAF基因的一个致癌突变被发现与散发性结直肠癌有关，表现出MMR缺陷。本研究的目的是评价BRAF V600E突变分析在初诊结直肠癌患者MSH2/MLH1基因突变携带者识别中的作用。方法：在EPICOLON人群研究中，对伴有MMR缺陷(微卫星不稳定和/或MLH1/MSH2蛋白表达缺失)的结直肠癌患者进行BRAF V600E突变分析。根据MSH2/MLH1胚系突变的存在，评估不同策略的有效性和效率。结果：在1222例伴有微卫星不稳定(n=111)或蛋白表达缺失(n=81)的结直肠癌患者中，119例检测到MMR缺陷。22例患者(18.5%)检测到BRAF突变。有明确胚系突变的患者无一例发生BRAF突变。无论采用哪种策略来识别MSH2/MLH1基因携带者，在这些患者中引入BRAF分析都会略微提高他们的有效性。在对MMR缺陷患者进行胚系基因测试之前，引入了BRAF突变分析，大大降低了检测到的每个突变的成本。结论：检测BRAF V600E突变可以简化和提高遗传性非息肉病性结直肠癌基因检测的成本效益，特别是在家族史不完整或未知的患者中。
Background & Aims: Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients. Methods: BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations. Results: MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected. Conclusions: Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.