Familial predisposition:

Although most gastric cancers are sporadic, aggregation within families occurs in approximately 10 percent of cases. Truly hereditary (familial) gastric cancer accounts for 1 to 3 percent of the global burden of gastric cancer and comprises at least three major syndromes:

  • Hereditary diffuse gastric cancer (HDGC),
  • Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and
  • Familial intestinal gastric cancer (FIGC).

The risk of developing gastric cancer is high in these families, but only HDGC is genetically explained.

Hereditary diffuse gastric cancer:

HDGC is an inherited form of diffuse type gastric cancer, a highly invasive tumor that is characterized by late presentation and a poor prognosis.

Germline truncating mutations in the cadherin 1 (CDH1) gene, which encodes the cell adhesion protein E-cadherin, have been identified in approximately 19 to 50 percent of affected kindreds who meet the clinical criteria for HDGC as described by the International Gastric Cancer Linkage Consortium (IGCLC).The risk of gastric cancer in asymptomatic carriers of a pathogenetic CDH1 mutation who belong to families with highly penetrant HDGC is sufficiently high to warrant prophylactic gastrectomy. Surgery is usually recommended between the age of 20 and 30, although factors other than age, including fertility considerations, the family phenotype (especially the age of onset of clinical cancer in probands), physical fitness, and preexisting nutritional disorders, should also be taken into account.Women in these affected families are also at high risk of developing breast cancer, predominantly lobular.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was initially identified in 2012 and is characterized by the autosomal dominant transmission of fundic gland polyposis (including dysplastic lesions, intestinal type gastric adenocarcinoma, or both) that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or another hereditary gastrointestinal cancer syndrome.

Familial intestinal gastric cancer (FIGC):

FIGC should be considered a potential diagnosis when histopathologic reports denote intestinal type gastric cancers that segregate within families without gastric polyposis. An autosomal dominant inheritance pattern has been noted in many such families. The genetic cause is unknown, and few recommendations are available for the clinical management of these patients.

Other hereditary cancer syndromes:

Gastric cancer has also been described in association with certain other inherited cancer syndromes, including Lynch syndrome (hereditary nonpolyposis colorectal cancer), FAP, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, juvenile polyposis, hereditary breast and ovarian cancer syndrome, and possibly, phosphatase and tensin homolog (PTEN) hamartoma tumor (Cowden) syndrome, but these are all fairly rare causes of gastric cancer.

Gastric polyps:

Gastric polyps are typically found incidentally when an upper gastrointestinal endoscopy is performed for an unrelated indication; only rarely do they cause symptoms or other clinical signs. Nevertheless, their discovery can be important since many polyps have malignant potential.

Blood group:

The role of genetic factors was first suggested by the study of blood groups and determinants of chronic gastritis. Individuals of blood group A have been known for decades to show an approximately 20 percent excess of gastric cancer compared with those of group O, B, or AB . They also show a similar increase in the rate of pernicious anemia. Some data suggest that group A may be particularly associated with diffuse-type gastric cancer. It is possible that the observed associations are not due to the blood group antigens themselves but to the effects of genes closely associated with them.

Hypertrophic gastropathy and immunodeficiency syndromes:

Hypertrophic gastropathy (including Ménétrier’s disease) and various immunodeficiency syndromes have been linked with gastric cancer.

Gastric ulcer:

An association between benign gastric ulcers and gastric cancers probably reflects common risk factors (ie, mainly H. pylori infection).

Pernicious anemia:

Pernicious anemia, a sequela of autoimmune chronic atrophic gastritis directed against hydrogen-potassium ATPase in the gastric parietal cells, is associated with an increased risk of intestinal type gastric cancer. A two- to sixfold excess risk has been reported, but as with other predisposing conditions, the actual degree of risk varies with the duration of disease and geographic location.

Pernicious anemia is also associated with an increased risk of gastric neuroendocrine tumors, presumably due to prolonged achlorhydria resulting from parietal cell loss, compensatory hypergastrinemia, and argyrophilic cell hyperplasiaH