Is hereditary diffuse gastric cancer (HDGC) an autosomal dominant or recessive condition?

Hereditary Diffuse Gastric Cancer (HDGC) Inheritance Pattern

Hereditary Diffuse Gastric Cancer (HDGC) is an autosomal dominant cancer syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. 1

Genetic Basis and Inheritance

• HDGC is primarily caused by inactivating germline mutations in the CDH1 tumor suppressor gene, which encodes E-cadherin, a transmembrane protein localized to adherens junctions in epithelial tissues 1
• The inheritance pattern is autosomal dominant, meaning that a single copy of the mutated gene is sufficient to cause the disease predisposition 1
• Pathogenic variants in CTNNA1 (encoding α-catenin) occur in a minority (1-2%) of HDGC families, also following an autosomal dominant inheritance pattern 1

Penetrance and Risk

• The cumulative risk of diffuse gastric cancer for CDH1 mutation carriers by age 80 is approximately 70% for men and 56% for women 1
• Female carriers also have a 42% lifetime risk of developing lobular breast cancer by age 80 1
• The age of onset for HDGC can be highly variable, ranging from 14-85 years 1
• Penetrance is relatively high with a 70-80% lifetime risk for gastric cancer 2

Clinical Management Implications

• Due to the autosomal dominant inheritance pattern, first-degree relatives of affected individuals have a 50% chance of inheriting the pathogenic variant 1, 3
• Genetic testing is recommended for families that meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria 1:
  • Two or more documented cases of gastric cancer at any age in first- or second-degree relatives, with at least one confirmed diffuse gastric cancer
  • Personal history of diffuse gastric cancer before age 40
  • Personal or family history of diffuse gastric cancer and lobular breast cancer, with one diagnosed before age 50 1
• Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers 1, 4
• Endoscopic surveillance in expert centers can be offered to patients who wish to postpone surgery or whose risk is not well defined 1

Important Considerations

• The autosomal dominant inheritance pattern means that each child of an affected individual has a 50% chance of inheriting the mutation 1, 3
• Genetic counseling should be provided to at-risk individuals to discuss inheritance patterns, penetrance, and management options 5
• Testing for germline CDH1 alterations should include both DNA sequencing and large rearrangement analysis 1
• Age of genetic testing for at-risk relatives should consider the earliest age of cancer onset in the family, with testing from late teens or early 20s favored in families with early-onset diffuse gastric cancer 1

Research Developments

• Researchers are actively investigating the consequences of E-cadherin loss in gastric epithelium to identify potential molecular drivers of HDGC development 4
• Several signaling pathways, including Notch and Wnt, have been shown to facilitate the progression of HDGC, potentially offering targets for future therapeutic approaches 3
• These discoveries provide promise for chemoprevention strategies, biomarker discovery, and targeted therapies for diffuse-type gastric cancer 4, 6