BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing
BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing
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DOI：
10.1136/jmg.2004.020651
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发表时间：
2004-09-01
影响因子：
4
通讯作者：
Schwartz, S
中科院分区：
文献类型：
--
作者：
Domingo, E;Laiho, P;Schwartz, S
背景资料：根据遗传性非息肉病性结直肠癌（HNPCC）诊断的国际标准，具有家族史或早期发病的结直肠肿瘤显示高微卫星不稳定性（MSI-H）的癌症患者应接受遗传咨询，并提供DNA修复基因（主要是MLH 1和MSH 2）的生殖系突变检测。最近，在RAS/RAF/MAPK通路的激酶编码基因BRAF中发现了一个致癌的V600 E热点突变，该突变与散发性MSI-H结肠癌相关，但其与HNPCC的关系仍有待进一步阐明。通过自动测序分析了206例散发性MSI的结直肠癌中BRAF-V600 E突变。H和111例MLH 1和MSH 2已知种系突变的HNPCC病例。结果：在40%（82/206）的散发性MSI-H肿瘤中发现BRAF-V600 E热点突变，而在111例HNPCC肿瘤和45例MSH 2异常的HNPCC中均未发现BRAF-V600 E热点突变。在结直肠MSI-H肿瘤中检测到V600 E突变，反对MLH 1或MSH 2基因中存在生殖系突变。因此，在V600 E阳性的病例中，如果没有其他显著证据（如符合严格的Amsterdam标准）提示MMR相关的HNPCC，则可以避免筛查这些错配修复（MMR）基因。在这种情况下，BRAF热点的突变分析是一种可靠、快速和低成本的策略，它简化了HNPCC的基因检测。
Background: According to the international criteria for hereditary non-polyposis colorectal cancer (HNPCC) diagnostics, cancer patients with a family history or early onset of colorectal tumours showing high microsatellite instability (MSI-H) should receive genetic counselling and be offered testing for germline mutations in DNA repair genes, mainly MLH1 and MSH2. Recently, an oncogenic V600E hotspot mutation within BRAF, a kinase encoding gene from the RAS/RAF/MAPK pathway, has been found to be associated with sporadic MSI-H colon cancer, but its association with HNPCC remains to be further clarified.Methods: BRAF-V600E mutations were analysed by automatic sequencing in colorectal cancers from 206 sporadic cases with MSI-H and 111 HNPCC cases with known germline mutations in MLH1 and MSH2. In addition, 45 HNPCC cases showing abnormal immunostaining for MSH2 were also analysed.Results: The BRAF-V600E hotspot mutation was found in 40% (82/206) of the sporadic MSI-H tumours analysed but in none of the 111 tested HNPCC tumours or in the 45 cases showing abnormal MSH2 immunostaining.Conclusions: Detection of the V600E mutation in a colorectal MSI-H tumour argues against the presence of a germline mutation in either the MLH1 or MSH2 gene. Therefore, screening of these mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC.