Germline CDH1 Variants and Lifetime Cancer Risk (2024)

• ¹Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

• ²Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

• ³Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois

• ⁴Cancer Genetics and Genomics, Stanford University, Stanford, California

• ⁵Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston

• ⁶Division of Gastroenterology, Massachusetts General Hospital, Boston

• ⁷Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California

• ⁸Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia

• ⁹Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Key Points

Question In individuals with CDH1 gene variants, what is the lifetime risk of gastric and breast cancer?

Findings In this multicenter, retrospective cohort and modeling study that included 213 families with more than 1 family member with a CDH1 gene variant, the cumulative risk of diffuse gastric cancer by age 80 years was 7% to 10%, and the cumulative risk of breast cancer among female carriers was 37%.

Meaning Among individuals with a CDH1 gene variant, the risk of gastric cancer was lower than previously described, while risk of breast cancer among female carriers was similar to previous estimates.

Importance Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.

Objective To describe gastric and breast cancer risk estimates for individuals with CDH1 variants.

Design, Setting, and Participants Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.

Main Outcomes and Measures Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.

Results A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).

Conclusions and Relevance Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Breast Cancer Oncology Women's Health Genetics and Genomics Gastroenterology Gastrointestinal Cancer Gastric Cancer Gastroenterology and Hepatology

Citation

Ryan CE, Fasaye G, Gallanis AF, et al. Germline CDH1 Variants and Lifetime Cancer Risk. JAMA. Published online June 14, 2024. doi:10.1001/jama.2024.10852

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