Biological Basis Of Hdgc Syndrome

HDGC is an autosomal dominant disorder with high penetrance, caused by germline mutations in the CDH1

gene encoding for E-cadherin. E-cadherin is a 120-kDa calcium-dependent transmembrane glycoprotein localized in lateral cell-cell contacts and enriched in the zonula adherens junctions.[1] The intact function of this adhesion molecule is crucial for the establishment and maintenance of epithelial tissue polarity, structural integrity, and cellular differentiation.1-1,2-1 It has five tandemly repeated extracellular domains that mediate intercellular adhesion through homophilic cellular interactions, and a cytoplas-mic domain that is responsible for the adhesive function of E-cadherin to the actin cytoskeleton through a complex with a, b, and g catenins.[2] E-cadherin mutations have been described for breast, gastric, endometrium, ovary, and thyroid carcinomas. However, frequent somatic mutations in CDH1 have been particularly implicated in the carcinogenesis of gastric carcinomas (in 40-83% of sporadic diffuse-type gastric cancer, but not in sporadic intestinal-type gastric cancer.[3,4]) and infiltrative lobular breast carcinomas.[5,6] In diffuse gastric carcinomas, the predominant mutations are exon skippings causing inframe deletion, in contrast to premature stop codon mutations identified in lobular breast cancer. Germline mutation of CDH1 gene in gastric cancer was originally discovered and reported in three Maori families in 1998.[7] The characteristics of the 18 families reported in the literature to have HDGC syndrome are summarized in Table 2. Both copies of the gene must be mutated to result in loss of function and carcinogenesis. A single copy of the mutated gene is inherited, and mutation or loss of promoter methylation of the second wild-type allele of the gene, through acquired genetic events, is required for loss of function and tumorigenesis. The accumulation of additional somatic mutations in other tumor-suppressor genes or oncogenes accounts for the phenotypic differences, and explains the increasing age-related penetrance of tumorigenic phenotype.

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