Clinical findings with implications for genetic testing in families with clustering of colorectal cancer
Clinical findings with implications for genetic testing in families with clustering of colorectal cancer
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DOI：
10.1056/nejm199808203390804
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发表时间：
1998-08-20
影响因子：
158.5
通讯作者：
Goetz, P
中科院分区：
文献类型：
--
作者：
Wijnen, JT;Vasen, HFA;Goetz, P
背景 DNA 错配修复基因（MSH2、MLH1、PIMS1、PMS2 和 MSH6）的种系突变会导致遗传性非息肉病性结直肠癌的易感性。我们评估了疑似患有遗传性非息肉病性结直肠癌的家族中 MSH2 和 MLH1 突变的患病率，并评估了临床结果是否可以预测基因检测的结果。 方法我们使用变性梯度凝胶电泳来鉴定 184 个具有熟悉的结直肠癌或与遗传性非息肉病性结直肠相关的其他癌症的家族中的 MSH2 和 MLH1 突变。 癌症。从所有家庭中获得了有关癌症部位、诊断时年龄和受影响家庭成员人数的信息。结果 在 184 个亲属中，有 47 个（26%）发现了 MSH2 或 MLH1 突变。与这些突变相关的临床因素包括结直肠癌诊断时的年龄较早、子宫内膜癌或小肠肿瘤的家族发生、患有结直肠癌或子宫内膜癌的家庭成员较多、单个家庭成员中存在多种结直肠癌或结直肠癌和子宫内膜癌，以及满足遗传性非息肉病诊断的阿姆斯特丹标准 结直肠癌（连续两代或以上的至少三名家庭成员必须患有结直肠癌，其中一人是另外两人的一级亲属；至少一名家庭成员必须在 50 岁之前诊断出癌症；并且必须排除家族性腺瘤性息肉病）。多变量分析表明，诊断结直肠癌的年龄较小、满足阿姆斯特丹标准以及亲属中存在子宫内膜癌是 MSH2 或 MLH1 种系突变的独立预测因素。这些结果被用来设计一个逻辑模型来估计 MSH2 和 MLH1 突变的可能性。 结论 对临床结果进行评估可以提高疑似患有遗传性非息肉病性结直肠癌的家族中 DNA 错配修复基因突变的检出率。 （N Engl J Med 1998；339：511-8。）(C)1998，马萨诸塞州医学会。
Background Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PIMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing.Methods We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familiar clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families.Results Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1.Conclusions Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer. (N Engl J Med 1998;339:511-8.) (C)1998, Massachusetts Medical Society.