Overview on new progress of hereditary diffuse gastric cancer with variants.

Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with variants. Accumulating evidence has demonstrated more than 100 germline variant types. E-cadherin encoded by the gene serves as a tumor suppressor protein. promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.