Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) due to constitutional variant 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 testing is recommended when the criteria below have been met and following confirmation of cancer diagnoses. At least one cancer should have confirmed histology. Where possible, other relevant cancers should also be confirmed. Histologically confirmed intestinal-type gastric cancer or non-lobular breast cancer cases should not be used to fulfil testing criteria as these are not part of HDGC. Individuals who meet the criteria for HDGC genetic testing should first have CDH1 analysed and, if no variant is identified, be considered for CTNNA1 analysis:

Family criteria*

  • Two or more cases of gastric cancer in family regardless of age, with at least one diffuse gastric cancer (DGC)
  • One or more case of DGC any age and one case of lobular breast cancer (LBC) under 70 years in different family members
  • Two nor more cases of LBC in family members under 50 years

*Family members must be 1st or 2nd degree blood relatives of each other. Where possible test an affected person. If there are no living affected relatives, consider tissue testing (tumour or normal) from an affected deceased relative. If these options are not possible, consider indirect testing in unaffected family members.

Individual criteria

  • DGC at age less than 50 years
  • DGC at any age in individuals of Māori ethnicity
  • DGC at any age with a personal or family history (1st degree) of cleft lip/cleft palate
  • DGC and LBC, both diagnosed under 70 years
  • Bilateral LBC/lobular carcinoma in situ, both diagnosed under 70 years
  • Gastric in situ signet ring cells and/or pagetoid spread of signet ring cells under 5o 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

Recent international guidelines are available. 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. Consider bilateral risk reducing mastectomy with or without reconstruction.

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 31 Dec 2020