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.

Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors

“…For most other genes, expression is typically expected to occur from both parental alleles without preference. Recent studies, however, have uncovered a potential role for random MAE, as well as differential allele-specific expression (DAE; i.e., a skew in allelespecific expression rather than complete monoallelic expression) in normal tissues as well as in some diseases, including cancer (3)(4)(5)(6)(7)(8)(9).…”

“…Expression of tumor suppressors and oncogenes is tightly regulated during the life of an individual, and it has been established that aberrant gene expression, such as that observed from loss of imprinting, can predispose individuals to cancer development (16). It is therefore reasonable to propose that aberrant gene expression caused by lack of one allele, MAE, could also lead to the development of cancer; indeed preliminary evidence exists to support this notion (7)(8)(9).…”

Rescue of wild-type E-cadherin expression from nonsense-mutated cancer cells by a suppressor-tRNA

“…Nonsense mutations occurred in 20% (n ¼ 25) of these cases (23 HDGC, 1 LBC and 1 EODGC). 4,[28][29][30] Under the hypothesis raised in the present work, all related nonsense mutation carriers may benefit from a target-designed sup-tRNA strategy ( Table 1).…”

Sequence analysis of the E-cadherin (CDH1) gene in a cohort of gastric cancers seen in the western cape

“…Patients who do not present with germline mutations are further analysed for large genomic deletions. These deletions have therefore been implicated as another possible contributing factor towards the pathogenesis of gastric cancer amongst the E-cadherin germline negative individuals (Oliveira et al, 2009;Pinheiro et al, 2010;Yamada et al 2011). It would therefore be interesting to explore the CDH1 large genomic deletions for future research.…”