Liquid Biopsies for the Personalized Management of Patients With Hereditary Diffuse Gastric Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Liquid Biopsies (Blood, Gastric Fluid) for the Personalized Management of Patients With Hereditary Diffuse Gastric Cancer: a Pilot Project

Conditions
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Hereditary Diffuse Gastric Cancer

Intervention / Treatment
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* Genetic: Liquid biopsies (blood, gastric fluid).


Participation Criteria
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Eligibility Criteria
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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 > 18years old Patients with no oncological history 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentric, prospective non-randomized study prognostic aim. Control group planned to have standard values.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Unaffected carriers of constitutional mutations<br>Patients with CDH1 or CTNNA1 germline pathogenic variant. No history of diffuse gastric cancer. | Genetic: Liquid biopsies (blood, gastric fluid).<br>* Next generation sequencing of a panel of diffuse gastric cancer genes, methylation analysis. Samples collected during routine screening endoscopy.<br>|
| Active Comparator: All patients with FOGD<br>without observation of macroscopic lesions paired with cases (age and sex) | Genetic: Liquid biopsies (blood, gastric fluid).<br>* Next generation sequencing of a panel of diffuse gastric cancer genes, methylation analysis. Samples collected during routine screening endoscopy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects in whom somatic mutations or methylation profiles are detected. |  | Over two years of surveillance | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Replicability of observations over successive endoscopies. Correlation between blood and gastric fluid. |  | Over two years of surveillance |