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New Estimates of Cancer Risk with Germline CDH1 Variants
Germline pathogenic (P) or likely pathogenic (LP) loss-of-function variants in the CDH1 gene are known to increase lifetime risks of gastric cancer and breast cancer, but the risk estimates to date (~50%) have been based on select populations, usually without consideration of the influence of cancer in other family members.
To better estimate these risks, researchers conducted a retrospective cohort study in North America involving 7323 individuals from 213 families that had more than one family member with a P/LP CDH1 variant. Genotyping was performed by certified diagnostic laboratories, with single-site analysis if a CDH1 variant existed in the family, single CDH1 gene analysis if personal and family history suggested hereditary diffuse gastric cancer, and multigene panel analysis if personal or family history overlapped with more than one syndrome.
Among individuals who carried a P/LP CDH1 variant, the lifetime risk of advanced gastric cancer was 10% in men and 7% in women. The risk was substantially higher (38%) in carriers with a strong family history of gastric cancer (three affected first-degree relatives), suggesting that other genetic factors may also be at play. The lifetime risk of breast cancer among female carriers was 37%.
Comment
The estimated risk for breast cancer in this study is similar to previous estimates, but the estimated risk for gastric cancer is much lower. Limitations of the analysis, per the investigators, include absence of complete clinical data, lack of information about the effects of risk-reducing surgery, and lack of information regarding ancestry and other potential familial factors affecting risk.
Current National Comprehensive Cancer Network guidelines recommend that individuals with P/LP variants of CDH1 undergo annual screening mammograms and consider breast magnetic resonance imaging with and without contrast starting at age 30; the option of risk-reduction mastectomy should also be discussed. How best to manage gastric cancer risk in these individuals in the absence of a strong family history is unclear.
Citation(s)
Author:
Ryan CE et al.
Title:
Germline CDH1 variants and lifetime cancer risk.
Source:
JAMA
2024
Jun
14; [e-pub].
(Abstract/FREE Full Text)
Empfohlen von
William J. Gradishar, MD