Hereditary Diffuse Gastric Cancer Syndrome

Abstract

This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…Heterozygous germline CDH1 mutations have been described in 18-40% of HDGC families [31][32][33][34][35]. The frequency of CDH1 mutations seems to be highly variable, which may be related to the variable incidence of GC across different geographic regions.…”

“…-E-catenin inhibition has been shown to destabilize adherens junctions, weakening the interaction between cells [38]. Currently, three families have been described with CTNNA1 germline mutations [35,39]. Loss of -E-catenin expression with preservation of E-cadherin has been observed in GC identified in CTNNA1 mutation carriers.…”

“…Germline BRCA2 mutations predispose to hereditary breast and ovarian cancer. In some families with BRCA2 mutations, an increased incidence of GC has been encountered [40][41][42][43], with one family fulfilling the HDGC criteria [35].…”

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

“…In families that met clinical criteria for HDGC, men carrying pathogenic CDH1 mutations were found to have a 70% cumulative risk of developing gastric cancer by age 80, while women have a 56% cumulative risk of developing gastric cancer by age 80 (Hansford et al. 2015). In addition to the risk of diffuse gastric cancer development, women carrying CDH1 mutations have a 42% cumulative risk of developing breast cancer (typically lobular breast cancer) (Hansford et al.…”

“…In addition to the risk of diffuse gastric cancer development, women carrying CDH1 mutations have a 42% cumulative risk of developing breast cancer (typically lobular breast cancer) (Hansford et al. 2015). …”