Abstract B010: Germline susceptibility to renal cell carcinoma and implications for genetic screening
Authors: Glennon Kate I. , Endo Mikiko , Usui Yoshiaki , Iwasaki Yusuke , Breau Rodney H. , Kapoor Anil , Tanguay Simon , Momozawa Yukihide , Riazalhosseini Yasser 
Published: August 2023

Abstract
Background: Genetic susceptibility to renal cell carcinoma (RCC) remains poorly understood and limited to specific hereditary cancer syndromes. Whereas few studies have investigated rare germline variants in specific populations, the majority of them have not taken into account differences between histological subtypes of RCC. Objective: To identify common risk-genes for RCC within the Canadian population, investigate their association to clinical annotations and outcomes, and compare gene-burden among RCC patients from various countries. Methods: We conducted targeted DNA sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 RCC patients (759 with clear cell and 201 with non-clear cell RCC) from Canada. We identified genes enriched in rare germline pathogenic variants (PVs) in RCC compared to a cancer-free control population (gnomAD, n=118148). Gene associations to RCC subtypes and clinical annotations were examined using Firth’s logistic regression models and Fisher’s exact tests, respectively. In addition, we compared prevalence of PVs in Canadian patients to those in previous studies from Japan (n=1632), the UK (n=1336) and the USA (n=254). Furthermore, we evaluated the performance of current criteria for RCC genetic screening for including patients with PVs in Canada, the US, and the UK. Results: We identified 39 germline PVs in 56 RCC patients from the Canadian cohort. Compared to cancer-free controls, PVs in MITF (OR: 212.3, 95% CI: 4.0-6.8, p= 1.44 × 10−9), CHEK2 (OR: 4.8, 95% CI: 1.0-2.1, p=3.94 × 10−5), and ATM (OR: 4.5, 95% CI: 0.7-2.2, p=0.016) genes were significantly enriched in patients with clear cell RCC, whereas PVs in FH (OR: 215.1, 95% CI: 4.2-6.4, p=6.14 × 10−9) were enriched in patients with non-clear cell RCC. We observed an association between PVs in DNA repair genes BRCA1, BRCA2 and ATM with the presence of metastasis in ccRCC (p=0.004) and RCC overall (p=0.003). Comparisons of gene-burden to other populations showed an enrichment for TP53 in RCC patients from Japan, while RCC patients from Canada showed an enrichment for CHEK2 and ATM. RCC patients from the US showed an enrichment for germline PVs in FH in comparison to Canadians. Notably, our analysis reveals that current criteria for referral to genetic screening for hereditary renal cancer fail to include the majority (73%) of patients harboring rare germline PVs in risk genes for RCC, both in Canada and globally. Conclusions: MITF, CHEK2, ATM, and FH were identified as risk-genes for RCC within the Canadian population, while germline mutations in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to identify up to 80% of patients with rare germline PVs.
Citation Format: Kate I. Glennon, Mikiko Endo, Yoshiaki Usui, Yusuke Iwasaki, Rodney H. Breau, Anil Kapoor, Simon Tanguay, Yukihide Momozawa, Yasser Riazalhosseini. Germline susceptibility to renal cell carcinoma and implications for genetic screening [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B010.