Yuan Y, Han H J, Zheng S, Park J G
Laboratory of Cell Biology, Cancer Research Center, Seoul National University College of Medicine, Korea.
Dis Colon Rectum. 1998 Apr;41(4):434-40. doi: 10.1007/BF02235756.
PURPOSE: The present study was designed to determine the frequency of germline mutations in the hMLH1 and hMSH2 genes in 31 families suspected of having hereditary nonpolyposis colorectal cancer who do not fulfill the criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer but in whom a genetic basis for colon cancer is strongly suspected and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. METHODS: Genomic DNAs were prepared from peripheral blood samples of patients who were tested. All coding exons and exon-intron borders of these two genes were screened, first with the polymerase chain reaction-single-strand conformation polymorphism method, followed by sequencing of the DNA fragments displaying an abnormal single-strand conformation polymorphism pattern. RESULTS: In 31 families with suspected hereditary nonpolyposis colorectal cancer, we found six different germline mutations in seven unrelated families, including one missense mutation and three frame-shift mutations in the hMLH1 gene and one missense mutation and one frame-shift mutation in the hMSH2 gene. Totally, frequency of mutation was 23 percent, 16 percent and 7 percent in the hMLH1 and hMSH2, respectively. Only one missense mutation of the hMSH2 gene was identified in 45 patients (2 percent) with sporadic early-onset colorectal cancer. The mutation detection rate in families with suspected hereditary nonpolyposis colorectal cancer was significantly higher than that of patients with sporadic early-onset colorectal cancer (P < 0.05). CONCLUSION: Our definition of suspected hereditary nonpolyposis colorectal cancer is useful in the diagnosis of hereditary nonpolyposis colorectal cancer and for identifying those families who need genetic presymptomatic diagnosis. Our results indicate that it may be important to perform DNA testing in families suspected of having hereditary nonpolyposis colorectal cancer. On the other hand, we only detected a low mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal cancer.
目的：本研究旨在确定31个疑似遗传性非息肉病性结直肠癌的家族以及45例散发性早发性结直肠癌患者中hMLH1和hMSH2基因种系突变的频率。这31个家族不符合遗传性非息肉病性结直肠癌国际协作组的标准，但强烈怀疑其结肠癌有遗传基础；45例散发性早发性结直肠癌患者在40岁之前患结直肠癌，且无任何结直肠癌家族史。 方法：从接受检测患者的外周血样本中制备基因组DNA。首先采用聚合酶链反应-单链构象多态性方法对这两个基因的所有编码外显子和外显子-内含子边界进行筛查，然后对显示异常单链构象多态性模式的DNA片段进行测序。 结果：在31个疑似遗传性非息肉病性结直肠癌的家族中，我们在7个无亲缘关系的家族中发现了6种不同的种系突变，包括hMLH1基因中的1个错义突变和3个移码突变以及hMSH2基因中的1个错义突变和1个移码突变。总的来说，hMLH1和hMSH2基因的突变频率分别为23%、16%和7%。在45例散发性早发性结直肠癌患者中仅鉴定出1个hMSH2基因的错义突变（2%）。疑似遗传性非息肉病性结直肠癌家族中的突变检测率显著高于散发性早发性结直肠癌患者（P<0.05）。 结论：我们对疑似遗传性非息肉病性结直肠癌的定义有助于遗传性非息肉病性结直肠癌的诊断，并有助于识别那些需要进行遗传症状前诊断的家族。我们的结果表明，对疑似遗传性非息肉病性结直肠癌家族进行DNA检测可能很重要。另一方面，我们在45例散发性早发性结直肠癌患者中仅检测到较低的突变率（2%）。
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