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Original Investigation
July 5, 2018

Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma

Author Affiliations
  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Sloan Kettering Institute, New York, New York
  • 3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. Published online July 5, 2018. doi:10.1001/jamaoncol.2018.1986
Key Points

Question  What is the prevalence of germline mutations in known renal cell carcinoma predisposition genes and other cancer-associated genes and what are the clinicopathologic factors associated with mutations?

Findings  In this cohort study of 254 patients with advanced renal cell carcinoma unselected for inherited cancer risk factors, 5.5% had mutations in renal cell carcinoma–associated genes and 10.5% in other cancer-associated genes. Among patients with non–clear cell renal cell carcinoma, 20.0% had any germline mutation, and 9% had a mutation diagnostic of hereditary leiomyomatosis (eg, FH mutation).

Meaning  The results of this study suggest that germline mutations may be frequent in patients with advanced renal cell carcinoma; genetic testing should be considered, especially for patients with advanced non–clear cell renal cell carcinoma.


Importance  Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown.

Objectives  To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations.

Design, Setting, and Participants  In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing.

Main Outcomes and Measures  Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status.

Results  Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (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). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non–clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing.

Conclusions and Relevance  Of patients with non–clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.