Hereditary diffuse gastric cancer: What the clinician should know

Abstract

Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.

Keywords: Hereditary diffuse gastric cancer, CDH1, CTNNA1, MAP3K6, Gastrectomy

Core tip: While the incidence of hereditary diffuse gastric cancer remains low, it is an important clinical entity to recognize due to its high pathogenicity and penetrance. The International Gastric Cancer Linkage Consortium has outlined CDH1 testing criteria and developed clinical utility gene cards to help clinicians manage such patients. Significant progress has been made in recent years and in future, testing of other genes is likely for CDH1-negative families. The mainstay of treatment for asymptomatic carriers of CDH1 pathogenic mutations remains prophylactic total gastrectomy. Future research should focus on better risk stratification and surveillance methods.