Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma.

RCC encompasses a set of histologically distinct cancers with a high estimated genetic heritability, of which only a portion is currently explained. Previous rare germline variant studies in RCC have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification that may significantly impact the interpretation and discovery of certain candidate risk genes. To evaluate the enrichment of germline PVs in established cancer-predisposing genes (CPGs) in clear cell and non-clear cell RCC patients compared to cancer-free controls using approaches that account for population stratification and to identify unconventional types of germline RCC risk variants that confer an increased risk of developing RCC. In 1,436 unselected RCC patients with sufficient data quality, we systematically identified rare germline PVs, cryptic splice variants, and copy number variants (CNVs). From this unselected cohort, 1,356 patients were ancestry-matched with 16,512 cancer-free controls, and gene-level enrichment of rare germline PVs were assessed in 143 CPGs, followed by an investigation of somatic events in matching tumor samples. Gene-level burden of rare germline PVs, identification of secondary somatic events accompanying the germline PVs, and characterization of less-explored types of rare germline PVs in RCC patients. In clear cell RCC (n = 976 patients), patients exhibited significantly higher prevalence of PVs in This systematic analysis supports the existing link between several RCC risk genes and elevated RCC risk manifesting in earlier age of RCC onset. Our analysis calls for caution when assessing the role of germline PVs in

Déclaration de conflit d'intérêts

COMPETING INTERESTS E.M.V.A. holds consulting roles with Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics and Serinus Bio; he receives research support from Novartis, Bristol-Myers Squibb and Sanofi; he has equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics and Serinus Bio; he has filed institutional patents on chromatin mutations, immunotherapy response, and methods for clinical interpretation. T.K.C. reports institutional and personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from: Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. Equity: Tempest, Pionyr, Osel, Precede Bio. CureResponse. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan. Medical writing and editorial assistance support may have been funded by Communications companies in part. No speaker’s bureau. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. T. K. C is also supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Charles River Associates, Schlesinger Associates, Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. R.G. has equity in Google, Microsoft, Amazon, Apple, Moderna, Pfizer, and Vertex Pharmaceuticals. B.R. has filed institutional patents on methods for clinical interpretation. Z.B. receives research support from Bristol Myers Squibb and imCORE/Genentech. He also reports honoraria from UpToDate. C.L. receives research funding from imCORE/Genentech outside the submitted work. The other authors declare no competing interests.