A Call for Better Screening for Hereditary Renal Cell Carcinoma


More than 20% of patients with non–clear cell RCC had a germline mutation, and half of this group could benefit from direct systemic therapy.

It may be time to adopt a broader approach to tumor and matched normal sequencing in patients with advanced renal cell carcinoma (RCC), according to a large new study. In an article published in JAMA, researchers report that germline mutations in patients with advanced RCC may be prevalent, and many of these mutations can be used to guide therapy. However, they are not being adequately detected.

Maria I. Carlo, MD, from Memorial Sloan Kettering Cancer Center, New York City, and colleagues assessed 254 patients and found that phenotype-directed or tumor-only testing failed to identify most of the patients with actionable mutations. This suggests that patients with non–clear cell RCC, in particular, may benefit from a broader approach to tumor-normal sequencing.

The researchers noted that identifying patients with hereditary RCC is paramount because it can help guide treatment decisions. However, there have been few investigations into the prevalence of cancer-related germline mutations in patients with advanced RCC. In addition, little is known about the phenotypes associated with some rare mutations.

Carlo and coinvestigators evaluated 254 patients with advanced RCC (American Joint Committee on Cancer stage III or IV disease) who were treated between October 1, 2015 and July 31, 2017. All patients (median age, 56 years) underwent germline sequencing. The patients ranged in age from 13 to 79 years, and 70.5% were male (N = 179).

Germline mutations were identified in 41 patients (16.1%). In this group, 14 patients (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (N = 9) and FH (N = 7).

Soroush Rais-Bahrami, MD, Assistant Professor of Urology and Radiology at the University of Alabama at Birmingham, believes these findings may be clinically relevant. “It is a very interesting study,” he said in an interview with Cancer Network. “This could lead to more directed treatments and better outcomes.” He said the findings point to a better way of identifying patients with advanced RCC who would benefit most from targeted therapies.

The study found genes not previously associated with RCC risk. Specifically, CHEK2 was overrepresented in patients with RCC compared with the general population (odds ratio, 3.0). Moreover, patients with non–clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 of 74 patients compared with 3 of 177 patients). 

The investigators reported that among patients with non–clear cell RCC, more than 20% had a germline mutation; further, 50% of those patients could benefit from direct systemic therapy. The researchers concluded that the current referral criteria for genetic testing may fail to identify a substantial proportion of patients with mutations.

“This really highlights how important it is to do genetic and germline testing. We can hone in on the genetic findings and that can make a difference,” said Rais-Bahrami. He added that the study results may lead to important new avenues of preventing advanced disease, and benefiting family members who get adequately screened.

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