HDGC

HDGC, or hereditary diffuse gastric cancer, is a hereditary cancer predisposition syndrome characterized primarily by a high risk of diffuse-type gastric cancer and an increased risk of lobular breast cancer in women. It is caused by pathogenic variants in the CDH1 gene, which encodes the cell adhesion protein E-cadherin. The condition is inherited in an autosomal dominant pattern with incomplete penetrance; the exact risk levels vary among families but are substantial for gastric cancer and, in female carriers, for breast cancer.

Clinical features of HDGC include the diffuse type of gastric cancer, which tends to be multifocal and may be difficult to detect with standard endoscopy because tumor cells often grow in scattered foci beneath an apparently normal mucosa. Signet-ring cell histology is common. In women who carry CDH1 mutations, there is an elevated risk of lobular breast cancer. Other cancers have been reported, but the association is less well established.

Diagnosis is based on genetic testing in individuals or families meeting international criteria for HDGC, primarily related to the pattern of gastric cancers in a family and the presence of diffuse-type disease. If a pathogenic CDH1 variant is identified, management focuses on risk reduction and early detection.

Management typically centers on prophylactic total gastrectomy for mutation carriers due to the high lifetime risk of diffuse gastric cancer, often after completion of childbearing and after thorough genetic counseling. For those who postpone surgery, intensive endoscopic surveillance with multiple targeted biopsies is used, though it may miss early cancers. Postoperative (post-gastrectomy) care requires ongoing nutritional monitoring and support. Female carriers should receive appropriate breast cancer surveillance, including MRI, given the elevated risk. HDGC remains a rare but well-defined hereditary cancer syndrome diagnosed through genetic testing and managed with multidisciplinary care.