Vasen H F A, Hendriks Y, de Jong A E, van Puijenbroek M, Tops C, Bröcker-Vriends A H J T, Wijnen J Th, Morreau H
Department of Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands.
Dis Markers. 2004;20(4-5):207-13. doi: 10.1155/2004/391039.
Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is a dominantly inherited syndrome characterized by the development of colorectal cancer, endometrial cancer and other cancers and the presence of microsatellite instability (MSI) in tumors. The Bethesda guidelines have been proposed for the identification of families suspected of HNPCC that require further molecular analysis. We have evaluated the yield of MSI-analysis in a large series of Dutch families suspected of HNPCC. We also analysed whether the loss of mismatch repair (MMR) protein detected by immunohistochemistry (IHC) of colorectal cancer (CRC) and endometrial cancer correlated with the presence of MSI and/or a MMR gene mutation. The results showed that the Bethesda criteria with a few modifications are appropriate to identify families eligible for genetic testing. In addition, we found that MSI and IHC-analysis of CRC using antibodies against MLH1, MSH2, MSH6 and PMS2 proteins are equally effective for identifying carriers of the known MMR gene defects. However, as long as the role of other putative MMR genes in hereditary CRC has not been elucidated, IHC-analysis cannot completely replace MSI. For this reason, we prefer MSI-analysis as first step in families suspected of HNPCC. On the other hand, in families fulfilling the revised Amsterdam criteria in which the probability of detecting a mutation is relatively high, we would recommend IHC as first diagnostic step because the result might predict the specific underlying MMR gene mutation. MSI or IHC-analysis of endometrial cancer alone was found to be less sensitive compared with these tests performed in colorectal cancer. Therefore, probably the best approach in the analysis of this cancer is to perform both techniques. The identification of HNPCC is important as it makes it possible to target effective preventative measures. Our studies showed that MSI and IHC analysis of colorectal and endometrial cancer, are reliable cost-effective tools that can be used to identify patients with HNPCC.
遗传性非息肉病性结直肠癌（HNPCC，林奇综合征）是一种显性遗传综合征，其特征为结直肠癌、子宫内膜癌和其他癌症的发生以及肿瘤中存在微卫星不稳定性（MSI）。已提出贝塞斯达指南用于识别疑似HNPCC且需要进一步分子分析的家族。我们评估了大量疑似HNPCC的荷兰家族中MSI分析的检出率。我们还分析了通过结直肠癌（CRC）和子宫内膜癌免疫组织化学（IHC）检测到的错配修复（MMR）蛋白缺失是否与MSI的存在和/或MMR基因突变相关。结果表明，经过一些修改的贝塞斯达标准适用于识别适合进行基因检测的家族。此外，我们发现使用针对MLH1、MSH2、MSH6和PMS2蛋白的抗体对CRC进行MSI和IHC分析在识别已知MMR基因缺陷携带者方面同样有效。然而，只要其他假定的MMR基因在遗传性CRC中的作用尚未阐明，IHC分析就不能完全替代MSI。因此，对于疑似HNPCC的家族，我们首选MSI分析作为第一步。另一方面，在符合修订后的阿姆斯特丹标准且检测到突变的概率相对较高的家族中，我们建议将IHC作为首选诊断步骤，因为其结果可能预测特定的潜在MMR基因突变。与在结直肠癌中进行的这些检测相比，单独对子宫内膜癌进行MSI或IHC分析的敏感性较低。因此，对这种癌症进行分析的最佳方法可能是同时进行这两种技术。识别HNPCC很重要，因为这使得采取有效的预防措施成为可能。我们的研究表明，对结直肠癌和子宫内膜癌进行MSI和IHC分析是可靠且具有成本效益的工具，可用于识别HNPCC患者。
