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Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma
NS. Vasudev, G. Scelo, KI. Glennon, M. Wilson, L. Letourneau, R. Eveleigh, N. Nourbehesht, M. Arseneault, A. Paccard, L. Egevad, J. Viksna, E. Celms, SM. Jackson, B. Abedi-Ardekani, AY. Warren, PJ. Selby, S. Trainor, M. Kimuli, J. Cartledge, N....
Language English Country United States
Document type Journal Article
NLK
Free Medical Journals
from 1995 to 1 year ago
Freely Accessible Science Journals
from 1995
Open Access Digital Library
from 1995-01-01
Open Access Digital Library
from 1995-01-01
- MeSH
- Carcinoma, Renal Cell * genetics therapy metabolism MeSH
- Humans MeSH
- Neoplasm Recurrence, Local genetics MeSH
- Mutation MeSH
- Von Hippel-Lindau Tumor Suppressor Protein genetics MeSH
- Kidney Neoplasms * genetics therapy metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
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.
Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic
Department of Human Genetics McGill University Montreal Québec Canada
Department of Oncology Pathology Karolinska Institutet Stockholm Sweden
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
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
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
References provided by Crossref.org
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