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

Abstract

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.

Quantification of APOBEC3 Mutation Rates Affecting the VP1 Gene of BK Polyomavirus In Vivo

“…This was illustrated particularly in patients 2017-20 and 2018-22, in whom the viral load profiles were highly similar, but while the APOBEC3A/B mutation rate tracked viral load in patient 2017-20, relatively few APOBEC3A/B mutations were detected in samples from patient 2018-22. These observations suggest that APOBEC3A/B editing rates vary between individuals in the context of BKPyV infection, and this may constitute a risk factor for the development of urothelial carcinoma subsequent to BKPyV infection, due to the role of APOBEC3A/B as a major mutagen in this cancer [37,38]. In terms of host genetics, there is a deletion/insertion polymorphism at the APOBEC3 locus, in which the deletion allele results in loss of APOBEC3B.…”

Mutational signatures and their association with survival and gene expression in urological carcinomas

“…The APOBEC-A-high SBS5 phenotype was linked to the absence of recurrences in a series of 62 high-grade, T1 non-muscle-invasive bladder cancers [26] . Non-COSMIC-based APOBEC mutational signatures have also been linked to improved outcomes in patients with advanced urothelial cancers, with most patients having BTCC [27] . To summarize, our results of a favourable prognosis in patients with a high number of SBS2 signatures are in line with the previously reported results regarding the behaviours of less aggressive cancers in APOBEC-high BTCC.…”

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion

“…Within our cohort, nearly half of the patients were associated with TMB values greater than 10 mutations/Mb. TMB has been used as a biomarker for the selection of different immune checkpoint inhibitors presenting a wider range of therapeutic strategies for the treatment of bladder cancer patients [ 27 , 28 ]. To our best knowledge, there are no studies exposing the clinical uses of TMB in Mexican patients with bladder cancer.…”