APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer

Frontiers in Oncology

Carlos Espinosa-Mendez¹  Henry J. Martell¹  Alejandro Sweet-Cordero¹  Eric J. Small²  Bradley Stohr²  Jonathan Chou²  Tanya Jindal²  Michelle Turski²  Arpita Desai²  James Grenert²  Nancy Joseph²  Lawrence Fong²  Jessica Van Ziffle²  Sima Porten²  Divya Natesan²  Emily Chan²  Li Zhang²  Vadim S. Koshkin²  Rahul Aggarwal²  Courtney Onodera²  Terence Friedlander²  Sarah Umetsu²  Anthony Wong²  Patrick Devine² 

[1] Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA, United States;Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, CA, United States;

关键词: bladder cancer;    APOBEC mutational signature;    tumor mutational burden;    next-generation sequencing;    urothelial cancer;    hypermutated;   

DOI  :  10.3389/fonc.2022.816706

来源: DOAJ

【 摘 要 】

IntroductionTumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.MethodsWe retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.ResultsAmong 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.ConclusionsIn a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.

【 授权许可】

Unknown