Aaltonen L A, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomäki P, Chadwick R B, Kääriäinen H, Eskelinen M, Järvinen H, Mecklin J P, de la Chapelle A
Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
N Engl J Med. 1998 May 21;338(21):1481-7. doi: 10.1056/NEJM199805213382101.
Genetic disorders that predispose people to colorectal cancer include the polyposis syndromes and hereditary nonpolyposis colorectal cancer. In contrast to the polyposis syndromes, hereditary nonpolyposis colorectal cancer lacks distinctive clinical features. However, a germ-line mutation of DNA mismatch-repair genes is a characteristic molecular feature of the disease. Since clinical screening of carriers of such mutations can help prevent cancer, it is important to devise strategies applicable to molecular screening for this disease.
We prospectively screened tumor specimens obtained from 509 consecutive patients with colorectal adenocarcinomas for DNA replication errors, which are characteristic of hereditary colorectal cancers. These replication errors were detected through microsatellite-marker analyses of tumor DNA. DNA from normal tissue from the patients with replication errors was screened for germ-line mutations of the mismatch-repair genes MLH1 and MSH2.
Among the 509 patients, 63 (12 percent) had replication errors. Specimens of normal tissue from 10 of these 63 patients had a germ-line mutation of MLH1 or MSH2. Of these 10 patients (2 percent of the 509 patients), 9 had a first-degree relative with endometrial or colorectal cancer, 7 were under 50 years of age, and 4 had had colorectal or endometrial cancer previously.
In this series of patients with colorectal cancer in Finland, at least 2 percent had hereditary nonpolyposis colorectal cancer. We recommend testing for replication errors in all patients with colorectal cancer who meet one or more of the following criteria: a family history of colorectal or endometrial cancer, an age of less than 50 years, and a history of multiple colorectal or endometrial cancers. Patients found to have replication errors should undergo further analysis for germ-line mutations in DNA mismatch-repair genes.
使人易患结直肠癌的遗传性疾病包括息肉病综合征和遗传性非息肉病性结直肠癌。与息肉病综合征不同，遗传性非息肉病性结直肠癌缺乏独特的临床特征。然而，DNA错配修复基因的种系突变是该疾病的一个特征性分子特征。由于对这类突变携带者进行临床筛查有助于预防癌症，因此制定适用于该疾病分子筛查的策略很重要。
我们前瞻性地筛查了从509例连续的结直肠腺癌患者获取的肿瘤标本，以查找遗传性结直肠癌特有的DNA复制错误。通过对肿瘤DNA进行微卫星标记分析来检测这些复制错误。对有复制错误患者的正常组织DNA进行筛查，以查找错配修复基因MLH1和MSH2的种系突变。
在509例患者中，63例（12%）有复制错误。这63例患者中有10例的正常组织标本存在MLH1或MSH2的种系突变。在这10例患者中（占509例患者的2%），9例有子宫内膜癌或结直肠癌的一级亲属，7例年龄在50岁以下，4例曾患结直肠癌或子宫内膜癌。
在芬兰的这组结直肠癌患者中，至少2%患有遗传性非息肉病性结直肠癌。我们建议对符合以下一项或多项标准的所有结直肠癌患者进行复制错误检测：有结直肠癌或子宫内膜癌家族史、年龄小于50岁、有多次结直肠癌或子宫内膜癌病史。发现有复制错误的患者应进一步分析DNA错配修复基因的种系突变。
