Research Papers:

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

Ming Yin _, Petros Grivas, Hamid Emamekhoo, Prateek Mendiratta, Siraj Ali, JoAnn Hsu, Monali Vasekar, Joseph J. Drabick, Sumanta Pal and Monika Joshi

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Oncotarget. 2018; 9:16891-16898. https://doi.org/10.18632/oncotarget.24738

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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

Correspondence to:

Monika Joshi, email: mjoshi@pennstatehealth.psu.edu

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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