Hereditary diffuse gastric cancer syndrome (CDH1-related)

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.

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.

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.

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, but further data is required to elucidate the phenotype associated with pathogenic variants in this gene.

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.

Criteria for genomic testing of CDH1 (R215: CDH1-related cancer syndrome) include:

• diffuse gastric cancer (at under 50 years);
• gastric in situ signet ring cells or pagetoid spread of signet ring cells at under 50 years;
• diffuse gastric cancer at any age with a personal history or first-degree relative (FDR) with cleft lip or cleft palate;
• personal history of both diffuse gastric cancer and lobular breast cancer at under 70 years;
• diffuse gastric cancer and one or more FDR/SDR with diffuse gastric cancer at any age;
• diffuse gastric cancer at any age and one or more FDR/SDR with lobular breast cancer at under 70 years;
• lobular breast cancer and one or more FDR/SDR has diffuse gastric cancer (one or more case occurred at under 70 years); or
• two cases of lobular breast cancer at under 50 years, such as bilateral or multiple ipsilateral tumours.

A small number of individuals in whom a clinical diagnosis of HDGC is suspected have been found to have pathogenic variants in CTNNA1, but testing of this gene is not routinely available through NHS laboratories until such a time as the phenotype and clinical management of carriers of variants in this gene are defined.

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.

• 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.
  • 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. 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, 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.

For clinicians

• For information on genomic testing for HDGC, see our ‘In the clinic’ article, Presentation: Patient with diffuse gastric cancer.
• NHS England: National Genomic Test Directory and eligibility criteria

References:

• Blair VR, McLeod M, Carneiro F and others. ‘Hereditary diffuse gastric cancer: updated clinical practice guidelines‘. Lancet Oncology August 2020: volume 21, issue 8, pages: e386–e297. DOI: 10.1016/S1470-2045(20)30219-9
• Stjepanovic N, Moreira L, Carneiro F and others. ‘Hereditary gastrointestinal cancers: ESMO Clinical practice guidelines for diagnosis, treatment and follow-up‘. Annals of Oncology 2019: volume 30, issue 10, pages 1,558–1,571. DOI: 10.1093/annonc/mdz233

For patients

• Cancer Research UK: Stomach cancer resources
• No Stomach for Cancer
• Oesophageal Patients Association: Gastric cancer