麻豆传媒

Current guidelines for renal cell carcinoma (RCC) recommend germline testing for certain patients, but the criteria may need updating, said authors of a study in .

Emerging evidence suggests that criteria such as a family history of RCC is not always predictive of a positive germline test, and scientists have identified new genes that may be involved in hereditary RCC, explained Charles B. Nguyen, MD, of the University of Michigan in Ann Arbor, and colleagues. "Thus, there is a need to better identify factors that predict which patients with RCC would benefit from genetic evaluation."

The team retrospectively analyzed data from 321 patients with RCC who underwent germline testing to try to find some of those additional factors.

"In this retrospective study, we report the prevalence and characterization of germline mutations and the associated clinicopathologic features in patients with a history of RCC who were referred for genetic counseling," the researchers wrote.

Nguyen discussed the findings and the implications in the following interview.

What did you find in terms of patients with pathogenic, likely pathogenic, and potentially targetable mutations?

Nguyen: Among the 321 patients in our study, 42 (13%) had a pathogenic or likely pathogenic germline variant. This is higher than older reports which showed that only 5-8% of patients with RCC have a germline mutation.

Our findings are similar to more recent studies which have consistently shown higher rates of germline mutations in RCC. Among those with a pathogenic or likely pathogenic germline variant, nearly half (45%) had a mutation that could be potentially targeted with an FDA-approved therapy for the gene or involved pathway or as part of an ongoing molecularly selected clinical trial.

Current guidelines use age criteria for germline testing. What did you find about age and pathogenic variants, and what are the potential implications of that?

Nguyen: Based on prior population studies, the National Comprehensive Cancer Network recommends genetic evaluation in patients with RCC who are diagnosed at age 46 or younger. However, we found that there was no statistically significant association with genetic testing outcomes when patients were categorized at an age cutoff of 46. The American College of Medical Genetics recommends genetic evaluation in patients with RCC who are diagnosed at an age less than 50. We similarly did not observe a statistically significant association with germline testing results at an age cutoff of 50.

Overall, our findings are similar to other retrospective studies which show that age alone may not fully capture patients with RCC who have a hereditary predisposition. Thus, age criteria for genetic testing may need to be optimized to better capture patients with hereditary RCC.

What factors were positively associated with pathogenic variants?

Nguyen: There was a statistically significant association between a positive genetic test and the presence of bilateral or multifocal RCC. This is not surprising given it is known that many hereditary RCC syndromes present with bilateral or multifocal disease.

We also found that patients who underwent targeted gene panel testing (<6 genes analyzed) had higher rates of pathogenic germline mutations compared with patients who underwent a broader, multigene panel.

Since our retrospective study spanned over two decades, most patients who had targeted panel testing underwent genetic evaluation in an earlier period when guideline recommendations and multigene panels were not available. Thus, genetic testing in the earlier years was guided by syndromic features suggestive of a hereditary RCC syndrome.

What do you recommend about genetic evaluation of patients with RCC based on your results?

Nguyen: Based on our study and findings by others, genetic evaluation should be at least considered in patients with RCC who have bilateral or multifocal tumors given the strong association with a hereditary predisposition. Patients with RCC who have syndromic features suggestive of an underlying hereditary RCC syndrome should also undergo genetic testing.

Genetic testing in patients with RCC who are above age cutoffs defined by clinical guidelines should still be considered for genetic evaluation, especially if other suspicious features are present.

Do you have any additional research ongoing or planned in this area?

Nguyen: We are looking to explore the prevalence of pathogenic mutations and predictive factors in a larger, multicenter cohort of patients with RCC. Genetic testing in RCC may be underutilized due to many reasons including the complexity and nuances of current guideline recommendations. Future quality improvement work to improve genetic testing in RCC by clinicians is planned.

Read the study here.