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Area of Science:

  • Oncology
  • Genetics
  • Gastroenterology

Background:

  • Hereditary cancer risk is primarily determined by germline gene variants, surpassing family history.
  • CDH1 gene variants are associated with hereditary diffuse gastric cancer (HDGC) and hereditary lobular breast cancer (HLBC).

Purpose of the Study:

  • To determine the prevalence of occult signet ring cell carcinoma in asymptomatic patients with hereditary lobular breast cancer (HLBC) due to CDH1 variants.
  • To assess gastric cancer risk in patients with CDH1 pathogenic or likely pathogenic (P/LP) variants, regardless of family history.

Main Methods:

  • A prospective cohort study enrolled 283 patients with CDH1 P/LP variants.
  • Patients were categorized into HLBC, HDGC, and mixed family history groups.
  • Prevalence of occult gastric cancer was assessed through risk-reducing gastrectomy and surveillance endoscopy.

Main Results:

  • Nearly all HLBC patients (93.8%) undergoing gastrectomy harbored occult gastric adenocarcinoma.
  • The prevalence of occult gastric cancer in asymptomatic HDGC patients was similarly high (94.7%).
  • High rates of occult gastric cancer were observed in CDH1 variant carriers even without a family history of gastric cancer.

Conclusions:

  • Germline CDH1 P/LP variants confer a highly penetrant gastric cancer phenotype, irrespective of family history.
  • These findings are crucial for genetic counseling of families with CDH1 variants, particularly those presumed to have HLBC.
  • Germline CDH1 variants are a strong indicator of gastric cancer risk, independent of family history.