Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer
Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer
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DOI：
10.1093/hmg/8.4.607
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发表时间：
1999-04-01
影响因子：
3.5
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Richards, FM;McKee, SA;Maher, ER
最近在三个患有家族性胃癌的毛利人家系中描述了E-钙粘蛋白基因（CDH 1）的遗传突变。家族性胃癌是遗传异质性的，并且不清楚非毛利人群体中胃癌易感性的比例是由于生殖系CDH 1突变。因此，我们筛选了8个家族性胃癌激酶的英国和爱尔兰起源的生殖系CDH 1突变，所有16个外显子和侧翼序列的SSCP分析。每个家庭包含：（i）2例一级亲属胃癌，其中1例在50岁之前受累;或（ii）3例或3例以上胃癌，在2个家族中检测到新的生殖系CDH 1突变（无义和剪接位点）（25%）。这两种突变都被预测为截短了信号肽结构域中的E-钙粘蛋白蛋白。在一个家族中，有证据表明，除了6例胃癌外，还有1例CDH 1突变携带者在30岁时患上了结肠直肠癌。我们已经证实，CDH 1基因的生殖系突变导致非毛利人群体中的家族性胃癌。然而，只有少数家族性胃癌可以解释CDH 1突变。E-cadherin功能的丧失与散发性结直肠癌和其他癌症的发病机制有关，我们的研究结果提供了生殖系CDH 1突变易患早发性结直肠癌的证据。因此，CDH 1应该作为胃癌和结直肠癌遗传易感性的原因进行研究。
Inherited mutations in the E-cadherin gene (CDH1) were described recently in three Maori kindreds with familial gastric cancer, Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer, Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain, In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years, We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.