Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening

Purpose: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe.

Materials And Methods: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs.

Results: We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], = 3.94 × 10) and (OR, 4.5 [95% CI, 2.0 to 8.7], = .016) were significantly enriched in patients with clear cell, whereas PVs in (OR, 215.1 [95% CI, 64.4 to 597.8], = 6.14 × 10) were enriched in patients with non-clear cell RCCs. PVs in , , and were associated with metastasis ( = .003). Comparative analyses showed an enrichment of PVs in patients from Japan, of and in patients from Canada, the United States and the United Kingdom, and of and in the United States.

Conclusion: , , and are risk genes for RCC in the Canadian population, whereas PVs in / and are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.