CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk
CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk
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DOI：
10.1002/ijc.10176
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发表时间：
2002-03-10
影响因子：
6.4
通讯作者：
Vorechovsky, I
中科院分区：
文献类型：
--
作者：
Lei, HX;Sjöberg-Margolin, S;Vorechovsky, I
已经在许多上皮恶性肿瘤中鉴定了E-钙粘蛋白基因（CDH 1）的突变和表达减少。虽然在小叶乳腺癌中检测到体细胞CDH 1突变，频率范围为10- 56%，但在更常见的导管肿瘤中CDH 1改变似乎很罕见。在这里，我们分析了CDH 1的编码区突变，使用变性高效液相色谱法，发现4个突变83导管癌（5%）和3个突变25小叶癌（12%）。还分析了13例家族性小叶肿瘤患者的种系突变，但未检测到突变。在一项病例对照研究中，我们还测试了启动子多态性-161C-->A中的一个变体腺嘌呤等位基因是否对体外CDH 1的转录活性有影响，是否会产生任何可检测到的乳腺癌风险。乳腺癌患者之间等位基因频率无显著差异（326/1，152，28.3%）和对照组（190/696，27.3%，p > 0.05;相对危险度为1.05，95%可信区间为0.85-1.30）。在-152位点发现了一种新的启动子多态性，但变异胞嘧啶等位基因的频率在乳腺癌患者和对照组中也相似（0.71%对0.21%，p = 0.23）。使用含有核苷酸取代-161C/-152C和-161A/-152T的报告基因构建体的瞬时转染实验显示，与野生型构建体相比，转录活性仅轻微降低。这些结果并不支持CDH 1作为一个突出的低突变率癌症易感基因，但表明CDH 1突变有助于小叶和导管肿瘤的进展。(C)2002 Wiley-Liss，Inc.
Mutations and diminished expression of the E-cadherin gene (CDH1) have been identified in a number of epithelial malignancies. Although somatic CDH1 mutations were detected in lobular breast cancer with a frequency ranging from 10-56%, CDH1 alterations in more frequent ductal tumors appear to be rare. Here we have analyzed the coding region of CDH1 for mutations using denaturing high performance liquid chromatography and found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25 lobular carcinomas (12%). The germline of 13 patients with familial lobular tumors was also analyzed for mutations, but none were detected. In a case-control study, we also tested whether a variant adenine allele in the promoter polymorphism -161C-->A with a putative influence on the transcriptional activity of CDH1 in vitro confers any detectable risk of breast cancer. No significant difference in the allelic frequency between patients with breast cancer (326/1,152, 28.3%) and controls (190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval 0.85-1.30) was found. A novel promoter polymorphism was identified at position -152, but the frequency of the variant cytosine allele was also similar in patients with breast cancer and controls (0.71% vs. 0.21%, p = 0.23). Transient transfection experiments using reporter constructs containing the nucleotide substitutions -161C/-152C and -161A/-152T showed only a slight decrease in the transcription activity compared to the wild-type construct. These results do not support CDH1 as a prominent low-penetrance cancer susceptibility gene, but indicate that CDH1 mutations contribute to the progression of both lobular and ductal tumors. (C) 2002 Wiley-Liss, Inc.