Hereditary diffuse gastric cancer

In HDGC patients, familial clustering of the disease and an early age at disease onset (on average 38 years) are seen. A carcinoma with signet ring cells or of the diffuse type is seen by histopathology.

Every year approximately 6,300 women and 9,300 men in Germany are diagnosed with stomach cancer. Around 1-3% of all gastric cancers are hereditary (hereditary diffuse gastric cancer, HDGC).

HDGC is caused by loss-of-function mutations in the CDH1 gene. CDH1 is located on chromosome 16q22.1 and consists of 16 exons. The gene encodes the protein E-cadherin (epithelial cadherin), which occurs in epithelia, where it is involved in the formation of cell-cell contacts, among other things. It also plays a role in intracellular signal transduction and embryonic morphogenesis.

Pathogenic variants in the CDH1 gene are responsible for up to 40% of patients with hereditary diffuse gastric cancer. Carriers of pathogenic CDH1 variants have a 40-70% (men) and 60-80% (women) risk of developing gastric cancer in their lifetime. Women also have a 40-50% risk of developing lobular breast cancer. Furthermore, there is a correlation between the detection of CDH1 variants and the occurrence of cleft lip/palate. In a few families that previously tested negative for CDH1, pathogenic variants in the CTNNA1 gene have been detected. Apart from CDH1 and CTNNA1, no other genes are currently associated with the occurrence of HDGC.

Gastric cancer can also occur frequently in the context of HNPCC (Lynch) syndrome, Peutz‑Jegher syndrome or familial adenomatous polyposis.

According to the current S3 guideline on gastric cancer, the following criteria are indicative of suspected hereditary diffuse gastric carcinoma:

• Two or more first- and second- degree relatives with gastric cancer (regardless of age), one of whom who has diffuse gastric cancer, or
• One family member under the age of 40 with diffuse gastric cancer, or
• One family member with diffuse gastric cancer and another family member with lobular breast cancer, one of whom developed the disease before the age of 50.

Furthermore, testing should be considered for the following families:

• Two family members with lobular breast cancer before the age of 50, or one person with bilateral lobular breast cancer also before the age of 50, or
• Evidence of diffuse gastric carcinoma and cleft lip/palate in the family, or
• Histologically confirmed in situ signet ring cell carcinoma and/or pagetoid spread of signet ring cells.

Regular endoscopy or chromoendoscopy examinations are recommended for clinically confirmed HDGC. Prophylactic gastrectomy is indicated if a pathogenic CDH1 variant is detected. Women with a proven causative CDH1 germline variant should undergo intensive breast screening from the age of 30. Blood relatives and offspring of CDH1 carriers can be specifically tested for the causative variants detected in the family after genetic counselling.

• Leit­linienprogramm Onkologie: S3-Leitlinie Magenkarzinom, Langversion 2.01 (Konsultationsfassung), 2019
• Figueiredo et al. 2019, J Med Genet 56:199
• Kaurah et al 2018, , GeneReviews®
• van der Post RS et al. 2015, Gastroenterolo­gy 149:897
• van der Post RS et al. 2015, J Med Genet 52:361