A GERMLINE SUBSTITUTION IN THE HUMAN MSH2 GENE IS ASSOCIATED WITH HIGH-GRADE DYSPLASIA AND CANCER IN ULCERATIVE-COLITIS
A GERMLINE SUBSTITUTION IN THE HUMAN MSH2 GENE IS ASSOCIATED WITH HIGH-GRADE DYSPLASIA AND CANCER IN ULCERATIVE-COLITIS
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DOI：
10.1016/0016-5085(95)90280-5
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发表时间：
1995-07-01
期刊：
影响因子：
29.4
通讯作者：
RABINOVITCH, PS
中科院分区：
文献类型：
--
作者：
BRENTNALL, TA;RUBIN, CE;RABINOVITCH, PS
背景与目的：DNA 错配修复基因人类 MSH2 在患有遗传性非息肉病性结直肠癌的某些家族成员中显示出种系突变。病程>8年的溃疡性结肠炎（UC）患者患结直肠癌的风险增加；然而，尚未确定具体的体质易感基因异常。方法：在患有高度不典型增生或癌的 UC 患者中寻找种系人类 MSH2 异常。结果：对人 MSH2 的外显子 13 和侧翼区域进行直接测序后，在外显子 13 的 -6 内含子剪接受体位点显示种系 T 到 C 的替换。在 53 名患有高度不典型增生或癌症的 UC 患者中，有 14 名（26%）发现了这种替换，而 36 名不伴有不典型增生或癌症的高风险 UC 患者中，有 4 名（11%）发现了这种替换（P 小于或等于0.04），80 名健康成人献血者中有 7 名（9%）（P 小于或等于 0.003）。携带该替代的 UC 患者发生肿瘤的可能性是未携带该替代的 UC 患者的三倍。结论：人类 MSH2 基因中的内含子剪接位点替换存在于一般人群中，但在 UC 的情况下可能易患癌症。
Background & Aims: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of >8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. Methods: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. Results: After direct sequencing of exon 13 and flanking regions of human MSH2, a germline T to C substitution was shown at the -6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) (P less than or equal to 0.04) and in 7 of 80 healthy adult blood donors (9%) (P less than or equal to 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. Conclusions: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.