Introduction:

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

Methods:

Patients treated at our institution from 2016-2021 who were tested with commercially available germline panel of known hereditary RCC genes were analyzed. Patients with a personal or family history of a known hereditary syndrome as well as patients with no known history of a solid kidney tumor were excluded.  Comparative statistical analysis, multivariate logistic regression and odd ratios (OR) were used to determine which groups of patients have the highest frequency of positive germline alterations.

Results:

Over the study period, 396 patients underwent a RCC germline panel, of which 249 patients were eligible for analysis. Of these, 221 had at least one of the three 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%).  Increasing numbers of enrichment features raised the proportion of positive results; patients with no features had positive results in 7.1% of our cases, 1 feature 11.9%, 2 features 19.7% and 3 features 36.4%. For each additional enrichment feature, the odds of identifying a germline alteration increase by OR=2.12 (95%CI:1.28-3.62) (figure1). In a multivariate logistic regression model, the individual enrichment features had the following OR for positive 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.

Conclusion:

Patients presenting with early onset RCC, bilateral multifocal RCC and familial history of renal cancer are enriched populations with more frequent positive germline RCC alterations than the patients with RCC without one of these features. The odds of a positive germline alteration double with each additional enrichment feature. These findings support germline gene panel testing in these populations.

Funding: This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health