ATM/RB1 mutations predict shorter overall survival in urothelial cancer
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Ming Yin1,6, Petros Grivas2,7, Hamid Emamekhoo3, Prateek Mendiratta2, Siraj Ali4, JoAnn Hsu5, Monali Vasekar1, Joseph J. Drabick1, Sumanta Pal5 and Monika Joshi1
1Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA
2Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
3Department of Medicine, Division of Hematology-Oncology, University of Wisconsin Carbone Cancer Center, WI, USA
4Foundation Medicine, Cambridge, MA, USA
5Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
6Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
7Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA
Monika Joshi, email: email@example.com
Keywords: biomarkers; prognosis; bladder cancer; genomic alterations; next generation sequencing
Received: November 30, 2017 Accepted: March 02, 2018 Published: March 30, 2018
Background: Mutations of DNA repair genes, e.g. ATM/RB1, are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs.
Results: In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126).
Materials and Methods: Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS).
Conclusions: ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.
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