Background: There are large, unexplained variations in the incidence of renal cell carcinoma (RCC) across the globe. Germline genetic variation contributes strongly to individual differences in susceptibility to cancer; however, genetic risk factors for RCC are poorly understood. Likewise, little is known about differences between genetic basis of clear-cell (ccRCC) and other RCCs (nccRCC).
Methods: We investigated genetic susceptibility to RCC within the Canadian population through targeted sequencing of 19 RCC-related and 27 cancer-predisposition genes in a cohort of 960 patients, and compared potential risk-genes to those identified in other populations. We identified pathogenic variants (PVs) and conducted gene-based association tests between patients with RCC and non-cancer controls to identify risk-genes for RCC.
Results: We identified 39 germline PVs in 56 Canadian RCC patients. Compared to cancer-free controls, PVs in CHEK2, and ATM were significantly enriched in patients with ccRCC, whereas PVs in FH were enriched in patients with nccRCC. We observed an association between PVs in BRCA1/BRCA2 and ATM with the presence of metastasis. Gene-burden comparisons to other populations showed an enrichment for TP53 in RCC patients from Japan, while RCC patients from Canada, UK, and USA showed an enrichment for CHEK2 and ATM. RCC patients from the USA were enriched for germline PVs in FH and BAP1. We evaluated the performance of current genetic screening criteria for RCC. We reveal that current criteria for referral to genetic screening for hereditary RCC fail to include the majority (73%) of patients harboring rare germline PVs in risk genes for RCC.
Conclusions: This serves as the first investigation into RCC susceptibility within the Canadian population. These findings also provide insight into differences in global RCC-susceptibility, and that investigation of germline risk-genes in additional populations are needed to fully understand the heterogeneous susceptibility to RCC.
