PD18-10: Germline Testing in Renal Cell Carcinoma : Can Enrichment Features Help Predict Germline Alterations?

Alexis Rompre-Brodeur*, Nikhil Gopal, Jeunice Owens-Walton, Bradley Webster, Michael Daneshvar, Christopher Ricketts, Cathy Vocke, Laura Schmidt, Beth Ryan, W. Marston Linehan, Mark W. Ball, Bethesda, MD

Introduction: Renal cell carcinoma (RCC) resulting from a germline alteration accounts for 5-8% of RCC cases. Patients can present enrichment features that may help predict germline alterations, including early onset (EO) defined as age of diagnosis =46, bilateral multifocal (BMF), or familial history of renal cancer (FRC). Current recommendations for germline testing suffer from lack of high-quality evidence. We sought to characterize the frequency of germline alterations in these potentially enriched populations.

Methods: Patients treated at our institution from 2016-2021 tested with commercial germline panels for hereditary RCC genes were analyzed. Patients with personal or family history of hereditary RCC syndrome and patients with no history of a solid kidney tumor were excluded.  Comparative statistical analysis, multivariate logistic regression and odd ratios (OR) were used to determine which group had the highest frequency of germline alterations.

Results: Over the study period, 249 eligible patients underwent RCC germline testing. Of these, 221 had at least one potential enrichment features, including 110 with EO, 145 BMF and 64 FRC. Panel results were positive in 37(14.9%) patients, negative in 171(68.7%), or presented a variant of uncertain significance (VUS) in 41(16.5%).  Additional enrichment features increased the proportion of positive results; patients with no features had positive results in 7.1% of cases, 1 feature 11.9%, 2 features 19.7% and 3 features 36.4%. Each additional enrichment feature increased the odds of identifying a germline alteration by OR=2.12 (95%CI:1.28-3.62, p=0.04). In a multivariate logistic regression model, individual enrichment features had the following OR for germline alterations: FRC OR=2.92 (95%CI:1.35-6.31) p=0.006; BMF OR=1.68 p=0.199; EO OR=1.82 p=0.118. Simultaneous occurrence of EO+FRC was associated with an OR=2.89 (95%CI:1.03-7.65) p=0.036.

Conclusions: Patients with early onset, bilateral multifocal or familial history of renal cancer are enriched populations with more frequent germline alterations than patients without one of these features. The odds of a germline alteration doubles with each additional enrichment feature. These findings support germline panel testing in these enriched populations.

Source of Funding: Intramural Research Program, NCI, NIH.