Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer

The oncologist

article

Ming Yin¹  Monali Vasekar²  Edmund Folefac¹  Steven K. Clinton¹  Paul Monk¹  Monika Joshi²  Petros Grivas³  Qi-En Wang¹  Amir Mortazavi¹  Hamid Emamekhoo⁵  Sheldon L. Holder²  Joseph J. Drabick²  Michele Sue-Ann Woo⁶  Sumanta Pal⁷ 

[1] The Ohio State University Comprehensive Cancer Center;Penn State Cancer Institute;Cleveland Clinic Taussig Cancer Institute;University of Washington, Fred Hutchinson Cancer Research Center;University of Wisconsin Carbone Cancer Center;Foundation Medicine;City of Hope

关键词: ATM;    DNA repair;    Prognosis;    Bladder cancer;    Genomic alterations;   

DOI  :  10.1634/theoncologist.2019-0851

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM ) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different ( ATM : adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

【 授权许可】

CC BY|CC BY-NC