PURPOSE: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. EXPERIMENTAL DESIGN: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. RESULTS: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. CONCLUSIONS: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.

Carol Davila University of Medicine and Pharmacy Prof Dr Th Burghele Clinical Hospital Bucharest Romania

Centre National de Recherche en Génomique Humaine CEA Institut de Biologie Francois Jacob University Paris Saclay Evry France

Charles University Prague 1st Faculty of Medicine Institute of Hygiene and Epidemiology Prague Czech Republic

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Histopathology Cambridge University Hospitals NHS Foundation Trust Hills Road Cambridge United Kingdom

Department of Human Genetics McGill University Montreal Québec Canada

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Division of Cancer and Stem Cells School of Medicine University of Nottingham Nottingham United Kingdom

European Bioinformatics Institute European Molecular Biology Laboratory EMBL EBI Wellcome Trust Genome Campus Hinxton United Kingdom

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Institut National de la Santé et de la Recherche Médicale Toulouse France

Institute of Mathematics and Computer Science University of Latvia Riga Latvia

Institute of Pathology and Forensic Medicine Military Medical Academy Belgrade Serbia

Institute of Pathology School of Medicine Belgrade University of Belgrade Belgrade Serbia

Leeds Institute of Medical Research at St James's University of Leeds St James's University Hospital Leeds United Kingdom

N N Blokhin National Medical Research Centre of Oncology Moscow Russian Federation

National Institute of Public Health Bucuresti Romania

Newcastle Upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom

Pyrah Department of Urology Leeds Teaching Hospitals NHS Trust Lincoln Wing St James's University Hospital Leeds United Kingdom

Stockport NHS Foundation Trust Stockport United Kingdom

University Hospital Motol Prague Czech Republic

Victor Philip Dahdaleh Institute of Genomic Medicine at McGill University Montreal Québec Canada

World Health Organisation The Genomic Epidemiology Branch Lyon France

1078-0432. doi: 10.1158/1078-0432.CCR-29-7-HI PubMed

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