Highlight
– Rare pathogenic variants (RPVs) in 16 established cancer predisposition genes increase the risk of single and multiple primary cancers.
– This large population-based study used whole-exome sequencing data from over 180,000 UK Biobank participants.
– Individuals carrying RPVs showed significantly elevated odds for cancer, particularly multiple cancer diagnoses.
– Results underscore the clinical utility of multigene panel testing beyond family-based or clinically ascertained cases.
Study Background and Disease Burden
Cancer is a leading cause of morbidity and mortality worldwide. While common genetic variants contribute to cancer susceptibility, rare pathogenic variants in cancer predisposition genes often confer substantial increases in individual cancer risk. Traditionally, knowledge regarding these RPVs has mainly been derived from family-based or clinically ascertained cohorts, populations prone to ascertainment and selection biases. Such biases may limit the generalizability and accuracy of risk estimates and the understanding of variant penetrance.
Moreover, individuals with pathogenic variants may develop multiple primary cancers, a clinically important but less studied phenotype. Understanding the association of RPVs with both single and multiple cancer diagnoses in the general population can inform screening strategies, genetic counseling, and clinical management.
Study Design
This genetic association study utilized whole-exome sequencing data from the UK Biobank—a large, UK population-based cohort. Participants aged 40 to 69 years were recruited between 2006 and 2010, and the whole-exome sequencing release of 200,000 genomes in 2020 provided high-resolution genetic data.
The analysis focused on 183,627 White participants, chosen due to sufficient sample size and to minimize confounding from population stratification across ethnicity groups. Participants diagnosed with any cancer before or after biobank enrollment were identified using hospital inpatient records, cancer registries, and death registries up until March 2024.
A set of 96 previously implicated cancer predisposition genes were analyzed with genetic variation assessed. Two statistical approaches were applied: a robust optimal sequence kernel association test determined statistical significance, while Firth logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) to quantify associations.
Key Findings
Among 183,627 participants, 25,824 had at least one diagnosed cancer: 23,704 (91.8%) with a single cancer diagnosis and 2,130 (8.2%) with two or more primary cancers. The median age at cancer diagnosis was 62 years compared to 57 years in those without cancer.
Genetic variation in 16 cancer predisposition genes was significantly associated with one or more of the 11 selected cancer types (bladder, breast, central nervous system, colorectal, lung, melanoma, ovary, pancreatic, prostate, renal, thyroid). The genes included ATM, BARD1, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK2, HOXB13, MITF, MLH1, MSH2, MSH6, NF1, PALB2, RAD51C, and RAD51D.
The presence of an RPV in at least one of these genes increased the odds of having at least one cancer diagnosis nearly twofold (OR 1.87; 95% CI, 1.76-1.98). Importantly, the odds of multiple primary cancers were even higher in variant carriers (OR 2.56; 95% CI, 2.18-2.99). The carrier frequency was 6.28% among those with a single cancer and rose to 8.36% among individuals with multiple diagnoses.
This highlights that RPVs in these predisposition genes are not only associated with a greater risk of developing cancer but also predispose to multiple independent cancers. These findings are consistent with and extend existing knowledge from family-based cohorts into a general population setting, underscoring the robustness of these associations.
Expert Commentary
This study provides compelling evidence that multigene panel testing has clinical relevance in unselected populations, especially among individuals with multiple primary cancers. Given the higher odds ratios for multiple cancers, genetic testing strategies and counseling should consider these findings to personalize cancer risk assessment and surveillance.
However, the study’s limitation to White participants highlights an urgent need for large-scale genetic studies in diverse ethnic groups, as genetic architecture and variant penetrance may vary by ancestry. Additionally, while the associations are strong, absolute risk quantification and variant-specific penetrance require further investigation to optimize clinical guidelines.
The biological plausibility is supported by the roles of these predisposition genes in DNA repair, cell cycle regulation, and tumor suppression, consistent with multiorgan tumor susceptibilities.
Conclusion
This large population-based genetic association study demonstrates that rare pathogenic variants in 16 established cancer predisposition genes substantially increase the risk of single and multiple primary cancer diagnoses. These findings advance our understanding beyond family-based studies, mitigate the impact of ascertainment bias, and provide strong rationale for utilizing multigene panel testing in cancer patients, particularly those affected by multiple primary malignancies.
Future research should focus on diverse populations, long-term follow-up, and integration with polygenic risk scores and environmental factors to enhance personalized cancer risk prediction and prevention strategies.
References
Shevach JW, Xu J, Snyder N, Wei J, Shi Z, Tran H, Zheng SL, Beebe-Dimmer JL, Cooney KA. Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses. JAMA Oncol. 2025 Aug 28:e252879. doi: 10.1001/jamaoncol.2025.2879. Epub ahead of print. PMID: 40875208; PMCID: PMC12395360.