title: Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer.
abstract: 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.
authors: Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto 4200-465, Portugal.
authors: Hugo
authors: H
authors: Pinheiro
authors: Renata
authors: R
authors: Bordeira-Carriço
authors: Susana
authors: S
authors: Seixas
authors: Joana
authors: J
authors: Carvalho
authors: Janine
authors: J
authors: Senz
authors: Patrícia
authors: P
authors: Oliveira
authors: Patrícia
authors: P
authors: Inácio
authors: Leonor
authors: L
authors: Gusmão
authors: Jorge
authors: J
authors: Rocha
authors: David
authors: D
authors: Huntsman
authors: Raquel
authors: R
authors: Seruca
authors: Carla
authors: C
authors: Oliveira
mesh_terms: D000328:Adult; D000483:Alleles; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins