Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer
Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer
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DOI：
10.1093/hmg/ddp537
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发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Oliveira, Carla
中科院分区：
文献类型：
--
作者：
Pinheiro, Hugo;Bordeira-Carrico, Renata;Oliveira, Carla
遗传性弥漫性胃癌（HDGC）是一种以早发性弥漫性胃癌（DGC）和小叶型乳腺癌为特征的常染色体显性遗传性癌症易感综合征。E-cadherin（CDH 1）杂合子种系突变和缺失在40%的家庭中被发现。独立于CDH 1的改变，大多数HDGC肿瘤显示错误定位或缺乏E-钙粘蛋白的免疫表达，因此在CDH 1基因座未检测到的缺陷可能仍然涉及。我们的目的是确定是否CDH 1突变阴性先证者显示生殖系CDH 1等位基因特异性表达（ASE）的不平衡，使用单核苷酸引物延伸为基础的程序，并试图揭示潜在的分子缺陷。使用从21名无癌症个体和22名HDGC先证者（5名CDH 1突变携带者和17名CDH 1阴性）的血液中提取的RNA中的三个基因内SNPs进行CDH 1 ASE分析。生殖系启动子甲基化，缺失和单倍型相关的易感性在CDH 1位点进行了分析。来自无癌个体的两个CDH 1等位基因显示相等的表达水平，而单等位基因CDH 1表达或高等位基因表达不平衡（AI）存在于80%的CDH 1突变体和70.6%（n = 12）的CDH 1阴性HDGC先证者中。在25%表现出高CDH 1 AI的先证者中发现了生殖系缺失和启动子高甲基化。没有发现特定的单倍型与CDH 1高AI相关。生殖系CDH 1 AI在CDH 1突变阴性先证者中非常常见，但在无癌症个体中未见。这暗示了大多数突变阴性HDGC家族中的CDH 1基因座。
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer susceptibility syndrome characterized by early-onset diffuse gastric cancer (DGC) and lobular breast cancer. E-cadherin (CDH1) heterozygous germline mutations and deletions are found in 40% of families. Independent of CDH1 alterations, most HDGC tumours display mislocalized or absent E-cadherin immunoexpression, therefore undetected defects at the CDH1 locus may still be involved. We aimed at determining whether CDH1 mutation-negative probands display germline CDH1 allele-specific expression (ASE) imbalance, using a single-nucleotide primer extension-based procedure and tried to uncover the underlying molecular defect. CDH1 ASE analysis was performed using three intragenic SNPs in RNA extracted from the blood of 21 cancer-free individuals and 22 HDGC probands (5 CDH1 mutation carriers and 17 CDH1 negative). Germline promoter methylation, deletions and haplotype-related susceptibility at the CDH1 locus were analysed. Both CDH1 alleles from cancer-free individuals displayed equivalent expression levels, whereas monoallelic CDH1 expression or high allelic expression imbalance (AI) was present in 80% of CDH1 mutant and 70.6% (n = 12) of CDH1-negative HDGC probands. Germline deletions and promoter hypermethylation were found in 25% of probands displaying high CDH1 AI. No particular haplotype was found to be associated with CDH1 high AI. Germline CDH1 AI is highly frequent among CDH1 mutation-negative probands but was not seen in cancer-free individuals. This implicates the CDH1 locus in the majority of mutation-negative HDGC families.