Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations
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DOI：
10.1086/514847
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发表时间：
1997-08-01
影响因子：
9.8
通讯作者：
Fodde, R
中科院分区：
文献类型：
--
作者：
Wijnen, J;Khan, PM;Fodde, R
遗传性非息肉病性结直肠癌（HNPCC）是一种常见的常染色体显性遗传的癌症易感性疾病，以早发性结直肠癌为特征。已知四种DNA错配修复（MMR）基因（hMSH2、hMLH1、hPMS1或hPMS2）之一的种系突变会导致HNPCC。虽然在符合所谓阿姆斯特丹标准的HNPCC激酶中发现了这些基因的许多突变，但对这些基因在不满足这些标准但显示结直肠癌和其他癌症的明确家族聚集性的家族中的参与知之甚少。在这里，我们应用变性梯度凝胶电泳筛选hMSH2和hMLH1突变在两组HNPCC家庭，一组包括严格遵守阿姆斯特丹标准的家庭和另一组中，至少有一个标准不满足。有趣的是，hMSH2和hMLH1突变在49%的完全符合阿姆斯特丹标准的家族中被发现，而致病突变仅在8%的不完全符合标准的家族中被发现。与这些结果相一致，来自符合标准的患者的6个结肠直肠肿瘤中有4个显示微卫星不稳定性，而来自其他家族的11个肿瘤中只有3个显示这种不稳定性。虽然研究中包括的肿瘤数量很小，但MMR基因突变的频率在两组临床家族之间显示出明显的差异。这些结果也强调了阿姆斯特丹标准的实际重要性，它提供了一个有效的临床细分家庭之间的基础上，他们的机会进行hMSH2或hMLH1突变，并承担重要后果的遗传检测和咨询和管理的结直肠癌家庭。
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germline mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.