期刊
HUMAN MOLECULAR GENETICS
卷 19, 期 5, 页码 943-952出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp537
关键词
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资金
- Portuguese Foundation for Science and Technology (FCT) [PTDC/ SAU-GMG/72168/2006, SFRH/BD/1223/2007-HP, SFRH/BD/46462/2008-RC, SFRH/BD/ 44074/2008-JC, SFRH/BD/32984/2006-PO]
- Canadian Cancer Society/National Cancer Institute of Canada [018381]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-GMG/72168/2006] Funding Source: FCT
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.
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