Park J G, Vasen H F, Park K J, Peltomaki P, Ponz de Leon M, Rodriguez-Bigas M A, Lubinski J, Beck N E, Bisgaard M L, Miyaki M, Wijnen J T, Baba S, Lynch H T
Cancer Research Center, Cancer Research Institute, Seoul National University College of Medicine, Korea.
Dis Colon Rectum. 1999 Jun;42(6):710-5; discussion 715-6. doi: 10.1007/BF02236922.
The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.
We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I and II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp, at least one colorectal cancer case diagnosed before the age of 50, and occurrence of a hereditary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, or ovary) in family members. Criteria II consist of one colorectal cancer patient with at least one of the following: early age of onset (<40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling (one aged <50 years); and two siblings with other integral hereditary nonpolyposis colorectal cancer extracolonic cancers (one aged <50 years). A questionnaire was mailed to members of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria. For comparison the mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria in each institution was also obtained.
Data were obtained from eight different institutions (in 7 different countries). In a total of 123 patients from 123 families (67 families fulfilling Criteria I and 56 families fulfilling Criteria II), genetic testing for germline mismatch repair gene variants was performed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families fulfilling Criteria I was 28 percent (19/67). The mutation detection rate for families fulfilling Criteria II was 9 percent (5/56). In these eight institutions, the overall mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154).
The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and they can include extracolonic cancers. The results of this study suggest that families fulfilling Criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling Criteria II suggests that, using current techniques, genetic testing in these families is not practical.
本研究旨在确定疑似遗传性非息肉病性结直肠癌家族中错配修复基因的突变频率。
我们为疑似遗传性非息肉病性结直肠癌的家族制定了两条标准（标准I和标准II）。标准I包括至少两名患有结直肠癌的一级亲属，且至少具备以下情况之一：出现包括腺瘤性息肉在内的多个结直肠肿瘤、至少一例在50岁之前诊断出的结直肠癌病例、家族成员中发生遗传性非息肉病性结直肠癌的结外癌（子宫内膜、泌尿系统、小肠、胃、肝胆系统或卵巢）。标准II包括一名患有结直肠癌的患者，且至少具备以下情况之一：发病年龄早（<40岁）；索引患者或其兄弟姐妹（其中一人年龄<50岁）患有子宫内膜癌、泌尿系统癌或小肠癌；以及两名患有其他完整遗传性非息肉病性结直肠癌结外癌的兄弟姐妹（其中一人年龄<50岁）。向遗传性非息肉病性结直肠癌国际协作组的成员邮寄了一份问卷，以确定符合这些标准的家族中错配修复基因的突变检测率。为作比较，还获取了各机构中符合阿姆斯特丹遗传性非息肉病性结直肠癌标准的家族的突变检测率。
数据来自八个不同机构（分布在7个不同国家）。对123个家族中的123名患者（67个家族符合标准I，56个家族符合标准II）进行了种系错配修复基因变异的基因检测。在24个家族（20%）中鉴定出hMLH1或hMSH2基因的种系突变。其中，符合标准I的家族的突变检测率为28%（19/67）。符合标准II的家族的突变检测率为9%（5/56）。在这八个机构中，符合阿姆斯特丹遗传性非息肉病性结直肠癌标准的家族的总体突变检测率为50%（77/154）。
疑似遗传性非息肉病性结直肠癌的标准I具有可应用于核心家庭且可纳入结外癌的优点。本研究结果表明，应向符合标准I的家族提供基因检测。符合标准II的家族中相对较低的突变检测率表明，使用当前技术，对这些家族进行基因检测并不实用。
