| Title: | Monogenic and Polygenic Risk for Kidney Cancer in Two Large Biobanks |
| Journal: | European Urology Oncology |
| Published: | 20 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41864770/ |
| DOI: | https://doi.org/10.1016/j.euo.2026.03.004 |
Publication 17325
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Abstract
BACKGROUND: Pathogenic variants (PVs) in monogenic genes and polygenic risk scores (PRS) have been associated with kidney cancer risk. However, their joint contributions in the general population remain unclear.</p>
DESIGN, SETTING, AND PARTICIPANTS: Associations of kidney cancer with PVs in 15 core renal cell carcinoma (RCC) hereditary genes and 22 other cancer-susceptibility genes, and a published PRS (PGS004908) were evaluated in two large cohorts: the United Kingdom Biobank (UKB; N = 452 208) and the Genomic Health Initiative (GHI; N = 20 452).</p>
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards models were fitted using a time-to-event framework with age as the underlying time scale.</p>
RESULTS AND LIMITATIONS: In UKB, aggregated PVs in the 15 core-RCC genes, but not in the 22 cancer-susceptibility genes, were significantly associated with kidney cancer risk (p < 0.001 and p = 0.4, respectively). PRS, modeled as a continuous variable, was also significantly associated with kidney cancer (p < 0.001). These associations corresponded to a higher age-specific hazard and earlier accumulation of diagnoses across age. Substantial differences in kidney cancer incidence rates were observed across combined genetic risk strata; notably, non-carriers with high PRS had higher absolute incidence rates than PV carriers with low PRS. In a restricted cohort of participants free of kidney cancer at recruitment, addition of genetic risk factors to clinical risk factors significantly improved discrimination (C-statistic 0.67 vs 0.65, p < 0.001). The association of PRS with kidney cancer was replicated in the GHI across participants with both European and non-European ancestries.</p>
CONCLUSION: PRS meaningfully complements monogenic PVs in genetic risk assessment for kidney cancer and may improve risk stratification beyond established clinical factors.</p>
PATIENT SUMMARY: Many patients with kidney cancer do not carry rare inherited mutations. Our study shows that common genetic factors, captured in a PRS, can also identify high-risk individuals. Combining both rare mutations and common polygenic risks provides a more complete assessment of kidney cancer risk and may aid in earlier screening and prevention.</p>
15 Authors
- Jun Wei
- Ashley J Mulford
- Zhuqing Shi
- Huy Tran
- Annabelle Ashworth
- S Lilly Zheng
- Jim Lu
- Alan R Sanders
- Raj Bhanvadia
- Kristian Novakovic
- Conrad Tobert
- Brian Helfand
- Nirmish Singla
- Brian Lane
- Jianfeng Xu
Enabling scientific discoveries that improve human health