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90% of gastric cancers are adenocarcinomas, which are subdivided into diffuse (undifferentiated) and intestinal (well-differentiated) types (Lauren classification).

The World Health Organisation provides a more detailed division of gastric carcinomas, including:

  • tubular adenocarcinoma;
  • papillary adenocarcinoma;
  • mucinous adenocarcinoma;
  • poorly cohesive carcinoma (including signet ring cell carcinoma); and
  • mixed carcinoma.

In addition, a small proportion of gastric malignancies include gastro-intestinal stromal tumours (GISTs), lymphomas and neuroendocrine tumours.

Epidemiology of gastric cancer

There is significant global variation in the incidence of gastric cancer, with the highest rates observed in East Asia and Eastern Europe, with lower incidence in Western Europe and North America.

The majority of cases in the UK occur in patients over the age of 75 years. Gastric cancer associated with inherited cancer susceptibility syndromes typically present at an earlier age.

An estimated 54% of stomach cancers are associated with potentially modifiable risk factors, including tobacco use, alcohol use, Helicobacter pylori infection and diet. While incidence of gastric cancer is falling in North America and Western Europe, it remains a disease strongly linked to socioeconomic deprivation.

Genetics of gastric cancer

The majority of gastric cancers are sporadic, occurring as a result of somatic (tumour) mutations acquired during an individual’s lifetime. Such somatic mutations have arisen in the tumour and are not present constitutionally. They are therefore not present in the germline and cannot be passed on.

An estimated 10% of gastric cancers occur in familial clusters, and 1%–3% are caused as a result of hereditary cancer predisposition syndromes.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer susceptibility syndrome. Characterised by signet ring cell (SRC) cancer/diffuse gastric cancer, as well as lobular breast cancer, this syndrome is considered to account for less than 3% of global cases of gastric cancer. Pathogenic variants in CDH1 (encoding for E-cadherin) account for the majority of cases of HDGC, though pathogenic variants in CTNNA1 (encoding for α-E-catenin) have been reported in a small number of affected individuals.

Familial intestinal gastric cancer (FIGC) is considered when a strong family history of intestinal-type gastric cancer is observed in families without polyposis. The genomic cause of FIGC is currently poorly defined.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) causes stomach polyposis, a feature not observed in the majority of hereditary gastric cancers. GAPPS is considered to be a rare phenotypic presentation of FAP caused by a point mutation in the promoter 1B of the APC gene. This autosomal dominant cancer predisposition syndrome carries a significant risk of gastric polyps and adenocarcinoma but is not typically associated with colorectal polyps or adenocarcinomas.

Gastric cancer can arise as a result of other hereditary cancer syndromes, including Li-Fraumeni syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, Lynch syndrome, MUTYH-associated polyposis and juvenile polyposis.

Management implications of genomic testing

Hereditary diffuse gastric cancer

A diagnosis of HDGC has implications for cancer screening and risk reduction interventions:

  • CDH1 pathogenic variant carriers with a family history of diffuse gastric cancer 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 carriers of pathogenic CDH1 variants without a personal/family history of DGC.
  • It is recommended that testing and eradication of Helicobacter pylori be undertaken in all carriers.
  • The penetrance of pathogenic CTNNA1 variants remains poorly understood. Expert advice should be sought for management of carriers of 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.

Familial intestinal gastric cancer

  • There is a lack of evidence for surveillance recommendations for individuals with FIGC, though eradication of Helicobacter pylori is recommended in family members of patients presenting with gastric cancer at under 40 years of age.

Gastric adenocarcinoma and proximal polyposis of the stomach

  • Individualised management is advised for carriers of the GAPPS-associated APC gene pathogenic variant, although this typically includes endoscopic surveillance with random biopsies or polypectomy, and consideration of prophylactic gastrectomy depending on the familial phenotype.

Management implications for the other hereditary cancer syndromes mentioned above can be found under the individual linked resources.


For patients


Tagged: Constitutional mutations, Gastric cancer

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  • Last reviewed: 03/05/2022
  • Next review due: 03/05/2024
  • Authors: Samuel Luke Hill
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh