Trans-ethnic variation in germline variants of patients with renal cell carcinoma.

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.
Competing Interests: Declaration of interests S.Y., E.D.E., K.H., V.F., and S.N. are employees of Invitae Corporation, a testing laboratory that furnished the diagnostic test results used in this study. S.Y. reported other support from Invitae during the conduct of the study. E.D.E., K.H., and S.N. reported being shareholders of Invitae. J.E.G.: Astra-Zeneca, Helix Genetics, Ambry Genetics, Invitae Genetics, Myriad Genetics, Konica-Minolta, and Novartis Pharmaceuticals. H.Q.R. received honoraria from Ambry Genetics. David J. Kwiatkowski reports serving as a consultant for Novartis. B.A.M. discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He also received research support to the Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. G.S.: consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, EMD Serono, and Astellas/Agensys; research support to institution from AstraZeneca, Bayer, Amgen, Boehringer-Ingelheim, Janssen, Merck, Sanofi, and Pfizer; author for UpToDate; Steering Committee for AstraZeneca, BMS, Bavarian Nordic, and Astellas; speaker for OncLive, Research to Practice, and Physician Education Resource (PER). T.K.C. reported receiving institutional and personal funds from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products, Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis, and Takeda; reported receiving honoraria from the Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers Squibb/E.R. Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Genentech, Roche, Roche Products, Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UpToDate, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView, and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, and Lancet Oncology; having a consulting or advisory role at Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers Squibb/E.R. Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UpToDate, and NCCN; Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber, member of NCCN Kidney Panel and the GU Steering Committee, and past Chairman of the Kidney Cancer Association Medical and Scientific Steering Committee; medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel, among others); the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies and/or royalties potentially involved in research around the subject matter; CV provided upon request for scope of clinical practice and research. T.K.C. is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School, the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI, and various National Cancer Institute (NCI), Department of Defense (DOD), and foundations and industry grants. A.G. is supported by R01 CA227237, R01 CA244569, and the Louis B. Mayer Foundation. The remaining authors declare no competing interests.
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