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. 2018 Sep 1;4(9):1228-1235.
doi: 10.1001/jamaoncol.2018.1986.

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

Maria I Carlo  1 , Semanti Mukherjee  1   2 , Diana Mandelker  3 , Joseph Vijai  1   2 , Yelena Kemel  2 , Liying Zhang  3 , Andrea Knezevic  4 , Sujata Patil  4 , Ozge Ceyhan-Birsoy  3 , Kuo-Cheng Huang  3 , Almedina Redzematovic  1 , Devyn T Coskey  1 , Carolyn Stewart  1 , Nisha Pradhan  1 , Angela G Arnold  1 , A Ari Hakimi  5 , Ying-Bei Chen  3 , Jonathan A Coleman  5 , David M Hyman  1 , Marc Ladanyi  3 , Karen A Cadoo  1 , Michael F Walsh  1 , Zsofia K Stadler  1 , Chung-Han Lee  1 , Darren R Feldman  1 , Martin H Voss  1 , Mark Robson  1 , Robert J Motzer  1 , Kenneth Offit  1   2
Affiliations

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

Maria I Carlo et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Carlo reported serving a consulting or advisory role for Pfizer. Dr Mukherjee reported being employed within the past 2 years by Regeneron Pharmaceuticals. Dr Hyman reported serving a consulting or advisory role for Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, and AstraZeneca and receiving research funding from AstraZeneca, Puma Biotechnology, and Loxo. Dr Ladanyi reported serving a consulting or advisory role for Boehringer Ingelheim and AstraZeneca, receiving honoraria from Merck & Co, and receiving research funding from Loxo. Dr Cadoo reported receiving research funding from AstraZeneca. Dr Stadler reported serving a consulting or advisory role for Allergan, Genentech/Roche, Regeneron, Optos, and Adverum. Dr Lee reported serving a consulting or advisory role for Exelixis and receiving research funding from Pfizer, Eisai, and Bristol-Myers Squibb. Dr Feldman reported receiving research funding from Novartis and Seattle Genetics. Dr Voss reported serving a consulting or advisory role for Novartis, Calithera Biosciences, Natera, GlaxoSmithKline, Exelixis, Pfizer, and Alexion Pharmaceuticals and receiving travel and accommodation expenses from Novartis and Takeda, honoraria from Novartis, and research funding from Bristol-Myers Squibb and Genentech/Roche. Dr Robson reported serving a consulting or advisory role for AstraZeneca and McKesson and receiving travel and accommodation expenses from AstraZeneca, honoraria from AstraZeneca, and research funding from AstraZeneca, AbbVie, Medivation, Myriad Genetics, and InVitae. Dr Motzer reported serving a consulting or advisory role for Novartis, Pfizer, Eisai, Exelixis, and Merck & Co and receiving research funding from Bristol-Myers Squibb, Genentech/Roche, Pfizer, GlaxoSmithKline, Eisai, and Novartis. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Frequency and Distribution of Pathogenic Germline Mutations
Germline mutations were found in 41 patients (16.1%): RCC-associated mutations in 14 (5.5%) and other cancer-associated mutations in 27 (10.6%). Renal cell carcinoma (RCC)–associated germline mutations include mutations in BAP1, FH, MET, SDHA, SDHB, and VHL.
Figure 2.
Figure 2.. Pathogenic Mutations by Histologic Subtype
Two patients with BAP1 mutation had both clear cell and non–clear cell renal cell carcinoma; 1 patient with CHEK2 mutation had clear cell and non–clear cell renal cell carcinoma.
Figure 3.
Figure 3.. Somatic Mutations and Loss of Heterozygosity (LOH) in Patients With Germline Mutations
See this image and copyright information in PMC

Comment in

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