Activating somatic mutations and methylation profiles identified by liquid biopsies could identify CDH1 and CTNNA1 pathogenic variants carriers with invasive diffuse gastric cancer undetectable by upper G-I endoscopy.

Carriers of germline pathogenic variants in the CDH1 and CTNNA1 genes have the Hereditary Diffuse Gastric Cancer Syndrome. Asymptomatic carriers have at high lifetime risk of diffuse gastric cancer (30-70%). Screening upper gastrointestinal endoscopy, even with multiple random biopsies, misses signet ring cell cancer foci. Invasive cancers can thus go undetected. There is therefore a recommendation of total risk-reducing gastrectomy, at least in carriers with a family history of gastric cancer. Novel screening strategies are needed. In this pilot project, the investigators will perform liquid biopsies of both blood and gastric fluid in asymptomatic carriers who refuse gastrectomy and in controls. The investigators aim to show that somatic mutations in a panel of genes involved in gastric cancer and methylation profiles are detected in a subset of carriers, and not in controls. These could be indicative of invasive cancer undetected by endoscopy, and would thus be a strong argument for risk-reducing gastrectomy. On the contrary, in the absence of somatic mutations in liquid biopsies, endoscopic surveillance could continue.

Inclusion Criteria:

Case:

• Patient ≥ 18 years old
• CDH1 or CTNNA1 germline pathogenic variant.
• No history of diffuse gastric cancer.
• French social security.
• Ability to understand and willingness to sign a written informed consent document.

Volunteers:

• Patients ≥ 18 years old
• Patients with no oncological history
• Patients with macroscopically normal oeso-gastroduodenal fibroscopy
• French social security.
• Ability to understand and willingness to sign a written informed consent

Exclusion Criteria: for both arms

• Patients with cancer being treated
• Patients with metastatic cancer
• Medical contraindication to general anesthesia or FOGD (bleeding disorder, pregnant women )
• Patients under guardianship or curator

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.

Researchers who provide a methodologically sound proposal.