Wijnen J T, Vasen H F, Khan P M, Zwinderman A H, van der Klift H, Mulder A, Tops C, Møller P, Fodde R
Department of Human Genetics, Leiden University Medical Center, The Netherlands.
N Engl J Med. 1998 Aug 20;339(8):511-8. doi: 10.1056/NEJM199808203390804.
Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, 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.
We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial 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.
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.
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.
DNA错配修复基因（MSH2、MLH1、PMS1、PMS2和MSH6）中的种系突变会导致遗传性非息肉病性结直肠癌易感性增加。我们评估了疑似遗传性非息肉病性结直肠癌家族中MSH2和MLH1突变的患病率，并评估临床发现是否能够预测基因检测结果。
我们采用变性梯度凝胶电泳法，对184个有结直肠癌家族聚集性或与遗传性非息肉病性结直肠癌相关的其他癌症家族中的MSH2和MLH1突变进行鉴定。从所有家族中获取癌症发生部位、诊断年龄以及受影响家庭成员数量等信息。
在184个家族中的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年龄较小、家族中发生子宫内膜癌或小肠肿瘤、患有结直肠癌或子宫内膜癌的家庭成员数量较多、单个家庭成员患有多种结直肠癌或同时患有结直肠癌和子宫内膜癌，以及符合遗传性非息肉病性结直肠癌的阿姆斯特丹标准（在两代或更多代中至少有三名家庭成员患有结直肠癌，其中一人是另外两人的一级亲属；至少有一名家庭成员的癌症必须在50岁之前诊断；并且必须排除家族性腺瘤性息肉病）。多变量分析显示，结直肠癌诊断时年龄较小、符合阿姆斯特丹标准以及家族中存在子宫内膜癌是MSH2或MLH1种系突变的独立预测因素。这些结果被用于设计一个逻辑模型，以估计MSH2和MLH1发生突变的可能性。
对临床发现进行评估可以提高疑似遗传性非息肉病性结直肠癌家族中DNA错配修复基因突变的检测率。
