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Introduction

Characterised by signet ring cell (SRC) cancer/diffuse gastric cancer, as well as lobular breast cancer, hereditary diffuse gastric cancer (HDGC) syndrome is considered to account for less than 3% of global cases of gastric cancer.

Clinical features

HDGC is typically defined by the presence of a constitutional (germline) pathogenic CDH1 variant in either an isolated individual with diffuse type (rather than intestinal type) gastric cancer, or in a family with one or more diffuse gastric cancer or lobular breast cancer cases in first-degree or second-degree relatives.

The risk of diffuse gastric cancer (DGC) in individuals with pathogenic constitutional (germline) CDH1 variants ranges from 56%–70%. Affected individuals tend to develop DGC at a younger age (median age at diagnosis: 38 years) than in the general population, with the youngest reported case at age 14 years. In individuals with a pathogenic constitutional CDH1 variant and no family history of DGC, the risk of DGC is lower.

Females with pathogenic constitutional (germline) CDH1 variants have a lifetime risk of lobular breast cancer of 23%–68%, with an average age of diagnosis of 53 years. Individuals with pathogenic constitutional CDH1 variants also have an increased predisposition to cleft lip and/or palate.

Other cancers have also been reported in individuals with pathogenic CDH1 variants, including colorectal and appendiceal cancers, but the exact risks of these types of cancer have yet to be defined.

Epidemiology

HDGC is rare, with an incidence of 5–10 per 100,000 live births worldwide.

First described in 1998 among New Zealand Maori populations, the condition is observed in populations across the world. The majority of cases are attributed to constitutional (germline) pathogenic variants in the CDH1 gene.

A small number of individuals in whom HDGC is suspected have been found to have pathogenic CTNNA1 alterations.

The genetics of HDGC

HDGC is an autosomal dominant condition, the majority of which is caused by constitutional (germline) inactivating variants in the CDH1 tumour suppressor gene. The CDH1 gene encodes for E-cadherin, a transmembrane protein with a role in cell-cell adhesion, tension sensing and signal transduction.

Most variants in CDH1 causing HDGC are truncating variants, although other types of pathogenic variants have been described. This requires laboratory constitutional (germline) testing of the entire open reading frame, including copy number analysis of individual exons, to detect deletions or duplications.

CTNNA1 is a gene which encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The age of gastric cancer onset in confirmed CTNNA1 pathogenic variant carriers ranges from 22 to 72 years. The first study to provide CTNNA1 penetrance estimates reported up to a 57% lifetime risk of developing gastric cancer in families from European hereditary cancer registries

Criteria for genomic testing for hereditary diffuse gastric cancer (R215) include:

  • Diffuse gastric cancer (<50 years).
  • Gastric in situ signet ring cells or pagetoid spread of signet ring cells under 50 years.
  • Diffuse gastric cancer at any age with a personal history or FDR with cleft lip or cleft palate.
  • Double primary diffuse gastric cancer and lobular breast cancer (both <70 years).
  • Diffuse gastric cancer and ≥ 1 FDR/SDR with diffuse gastric cancer at any age.
  • Diffuse gastric cancer at any age and ≥1 FDR/SDR with lobular breast cancer <70 years.
  • Lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥ 1 case occurred < 70 years).
  • 2 cases of lobular breast cancer < 50 years e.g. multiple (not multifocal) ipsilateral tumours.
  • Bilateral lobular breast cancer < 70 years.
  • Diffuse gastric cancer in any individual of Maori ethnicity.

Pathogenic variants in a number of other genes are also associated with increased risk of intestinal-type gastric cancer, including APC (gastric adenocarcinoma and proximal polyposis of the stomach syndrome) and the mismatch repair genes (Lynch syndrome).

For information on genomic testing for HDGC, see Presentation: Patient with diffuse gastric cancer.

Management implications of genomic testing

  • At present, there are no therapeutic implications for identification of constitutional (germline) pathogenic variants in CDH1 in patients with diffuse gastric cancer or lobular breast cancer.
  • Identification of such pathogenic variants does, however, have implications for cancer screening and risk reduction interventions:
    • CDH1 pathogenic variant carriers from families with known HDGC should consider prophylactic total gastrectomy. This is generally offered in early adulthood, between the ages of 20 and 30 years.
    • Individuals wishing to postpone gastrectomy should be offered annual gastroscopy in an expert centre, by an experienced endoscopist with knowledge of HDGC, following international clinical practice guidelines by Blair and others 2020.
    • Considering the morbidity associated with prophylactic gastrectomy, this surgery should be cautiously considered in patients older than age 70, and in individuals with pathogenic CDH1 variants without a personal/family history of DGC.
    • It is recommended that testing for and eradication of Helicobacter pylori be undertaken.
    • The penetrance of pathogenic CTNNA1 variants remains poorly understood. Expert advice should be sought for management of individuals with such variants.
    • Given the risk of lobular breast cancer associated with pathogenic CDH1 variants, yearly breast surveillance with MRI should be undertaken from the age of 30 years. For women with a CDH1 GPV, bilateral risk-reducing mastectomy (BRRM) can be considered, but in general is not usually recommended under 30 yrs or after 60 years. Discussions should include consideration of other risk factors such as family history, and discussion of pros and cons of breast surveillance versus BRRM.
    • At present, screening for other types of cancer, including colorectal cancer, is not routinely recommended, unless otherwise warranted because of a strong family history of a particular cancer type.
  • The above recommendations are based on the international clinical practice guidelines published in 2020 and UKCGG guidelines. There are currently no NICE guidelines for management of HDGC carriers.
  • Referral to clinical genetics should be arranged for newly identified carriers of pathogenic or likely pathogenic variants in CDH1 or CTNNA1, to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Family planning implications

The Human Fertilisation and Embryology Authority has approved the use of pre-implantation genomic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one of the intended parents is a carrier of a likely pathogenic/pathogenic variant in CDH1. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children later in life.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 27/02/2025
  • Next review due: 27/02/2027
  • Authors: Samuel Luke Hill
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh