Jun Wei, Ashley Mulford, Zhuqing Shi, Huy Tran, Annabelle Ashworth, S. Lilly Zheng, Jim Lu, Alan R. Sanders, Raj Bhanvadia, Kristian Novakovic, Conrad M. Tobert, Brian Helfand, Nirmish Singla, Brian Lane, Jianfeng Xu
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. 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). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards models were fitted using a time-to-event framework with age as the underlying time scale. 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. CONCLUSION: PRS meaningfully complements monogenic PVs in genetic risk assessment for kidney cancer and may improve risk stratification beyond established clinical factors. 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.