The Changing Landscape of Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by the early onset of diffuse gastric cancer (DGC) and lobular breast cancer. HDGC is predominantly caused by germline truncating mutations in <i>CDH1</i>, which encodes the cell-cell adhesion protein, E-cadherin. Less frequent predisposing mutations are observed in the <i>CTNNA1</i> gene that encodes α-catenin. E-cadherin and α-catenin are components of the epithelial adherens junction and play important roles in cell adhesion, signal transduction, and cell architecture maintenance. The first step in DGC initiation in carriers of pathogenic <i>CDH1</i> and <i>CTNNA1</i> variants is the inactivation of wildtype <i>CDH1</i> or <i>CTNNA1</i> alleles, leading to the development of intramucosal gastric signet ring cell carcinomas (SRCCs). In the case of <i>CDH1</i> mutations, E-cadherin loss is associated with abnormal orientation of the mitotic spindle, which is believed to result in the displacement of dividing stem or progenitor cells out of the epithelial plane and into either the glandular lumen or lamina propria. Although these early stage pT1a SRCCs are generally indolent, they can acquire aggressive traits that precede a pattern of invasive growth. HDGC is clinically managed using an increasingly balanced approach involving endoscopic surveillance and prophylactic total gastrectomy. In this review, we discuss the range of predisposing germline HDGC variants and their effects, the mechanism of DGC initiation and growth, and current best practices for the diagnosis and management of this disease. Finally, we highlight emerging areas of research on the characterization, classification, and management of HDGC.