Historically, heritable cancer risk was generally considered binary, based on the presence or absence of a germline pathogenic or likely pathogenic variant (GPV) in a known inherited cancer susceptibility gene (CSG). However, it has become clear that risk is more complex and presents on a continuum based on specific GPVs, in conjunction with interactions with additional genomic risk modifiers, and many hormonal, lifestyle, and other environmental risk factors. Each of these factors have a variable contribution to risk in an individual with a CSG GPV and can be dynamic over a lifetime. In this article, the key concepts and considerations underpinning the paradigm shift in our understanding of inherited cancer risk is presented. Key concepts outlined in the article:
- GPVs in CSGs vary in their penetrance across organ sites and resultant influence on clinical management.
- Overall cancer risk in an individual with a CSG GPV can vary widely due to contributions from genetic factors such as the specific variant, wider genomic context (e.g., common risk alleles comprising polygenic risk scores), and modifiable and non-modifiable factors, including but not limited to, family history, age, environment, lifestyle, and hormonal factors.
- Cancer risk perception for an individual can be influenced by factors such as personal context, experience of hereditary cancer risk, and subjective experience of risk.
- The threshold for clinical intervention to either reduce cancer risk or initiate cancer surveillance requires assimilation of all contributing risk factors, consideration of medical context (i.e., other competing risks such as co-morbidities) and personalized counseling to enable individualized cancer risk management.
Preview our new article, which highlights key concepts in consideration of inherited cancer risk on a continuum at: https://www.gimjournal.org/article/S1098-3600(25)00306-5/fulltext
Pal, et al. Genet Med. 2026;28(3):101659. PMID: 41618953.
Article available at: https://pubmed.ncbi.nlm.nih.gov/41618953/.
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