Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) due to germline mutation of CDH1 was first described in 1998.

Only 1-3% of gastric cancer arises as a result of inherited cancer predisposition syndromes, including:

The lifetime risk of gastric cancer in these other syndromes is generally low except for HDGC and possibly GAPPS.


The first description of a molecular basis for HDGC was in a New Zealand Maori family in 1998. Linkage analysis implicated germline mutations in the CDH1 gene, on chromosome 16q22.1. This gene encodes for the tumour-suppressor protein E-cadherin. CDH1 mutations are responsible for approximately 40% of familial diffuse gastric cancer.


In HDGC the cumulative risk of advanced gastric cancer by the age of 80 years is reported to be 56% for women and 70% for men. In females with HDGC, a cumulative risk of lobular breast cancer (LBC) of 42% to 80 years of age is reported.

Laboratory testing

CDH1 mutation testing is generally advised in the following:

  • Two cases of gastric cancer at any age with at least one being confirmed to be diffuse gastric cancer
  • One case of DGC under the age of 40 years
  • Personal or family history of DGC and LBC, with one such cancer being diagnosed under the age of 50 years.

Testing can be considered in some additional situations as outlined here and in other clinical guidelines. E-cadherin tumour immunostaining staining is not useful in identifying potential HDGC families.

Presymptomatic CDH1 mutation testing is offered to appropriate individuals from the age of consent, generally 16–18 years.

Clinical management

For CDH1 mutation carriers, the current consensus recommendation is to consider ‘prophylactic’ gastrectomy, performed by an expert surgeon, in the third decade of life. This recommendation is made because, although asymptomatic CDH1 mutation carriers have been identified to have multifocal tiny signet ring cell cancers, these are not reliably detected at gastroscopy, even with advanced imaging techniques.

The risk of gastric cancer is less than 1% under the age of 20 years, so annual surveillance gastroscopy with targeted and random biopsies, according to an international protocol, is recommended for CDH1 mutation carriers aged 16-20 years.

Breast surveillance guided by a specialist with annual breast MRI (which can be combined with mammography) starting at age 30 years is recommended for women with a CDH1 mutation.

Carrying a CDH1 mutation has significant implications. Expert care is important but not always easy to access. Probands and families presenting purely with breast cancer in whom a CDH1 pathogenic mutation is identified (eg through breast cancer panel testing) represent a particular challenge with respect to management of their gastric cancer risk. Multidisciplinary centres of excellence need to work together with local centres to ensure the availability of appropriate genetic counseling and medical advice.

Content updated 18 Oct 2016