载脂蛋白B编辑酶催化多肽样蛋白突变特征和肿瘤突变负荷作为晚期尿路上皮癌患者临床结局和治疗反应的预测指标
APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer.
作者信息
Natesan Divya, Zhang Li, Martell Henry J, Jindal Tanya, Devine Patrick, Stohr Bradley, Espinosa-Mendez Carlos, Grenert James, Van Ziffle Jessica, Joseph Nancy, Umetsu Sarah, Onodera Courtney, Turski Michelle, Chan Emily, Desai Arpita, Aggarwal Rahul, Wong Anthony, Porten Sima, Chou Jonathan, Friedlander Terence, Fong Lawrence, Small Eric J, Sweet-Cordero Alejandro, Koshkin Vadim S
机构信息
Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, CA, United States.
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, United States.
出版信息
Front Oncol. 2022 Mar 7;12:816706. doi: 10.3389/fonc.2022.816706. eCollection 2022.
INTRODUCTION
Tumor 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.
METHODS
We 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.
RESULTS
Among 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 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months 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 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.
CONCLUSIONS
In 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.
引言
肿瘤突变负荷（TMB）和载脂蛋白B mRNA编辑酶催化多肽样（APOBEC）突变特征是晚期尿路上皮癌（aUC）患者潜在的预后标志物。它们在预测aUC特定治疗结果方面的效用值得进一步研究。
方法
我们回顾性分析了连续接受UCSF500检测的尿路上皮癌病例，这是一种机构检测方法，利用靶向DNA的杂交捕获富集技术检测479个常见癌症基因。将肿瘤突变负荷≥10个突变/Mb定义为高突变肿瘤（HM），同时评估其APOBEC突变特征，而由于肿瘤突变负荷低，未对非高突变（NHM）肿瘤进行评估。采用对数秩检验确定感兴趣的患者组之间总生存期（OS）和无进展生存期（PFS）是否存在差异。
结果
在75例接受UCSF500检测的aUC患者中，46例患者可评估肿瘤突变负荷，其中19例患者（41%）为高突变肿瘤，其余为非高突变肿瘤（27例）。另外29例患者的肿瘤突变负荷状态未知。在19例高突变患者中，所有16例可评估分析的患者均有APOBEC特征。将高突变患者（N = 19）与非高突变患者（N = 27）进行比较，高突变患者从诊断开始的总生存期有所改善（125.3个月对35.7个月，p = 0.06），但接受化疗患者的总生存期较差（7.0个月对13.1个月，p = 0.04）。将有APOBEC特征的患者（N = 16）与其余56例患者进行比较，其余患者包括27例非高突变患者和29例肿瘤突变负荷状态未知的患者，结果显示有APOBEC特征的患者从诊断开始的总生存期有所改善（125.3个月对44.5个月，p = 0.05），但接受化疗患者的总生存期较差（7.0个月对13.1个月，p = 0.05）。APOBEC特征和高突变状态均与免疫治疗反应无关。
结论
在一个使用机构二代测序（NGS）平台UCSF500评估的大型单机构aUC队列中，高突变肿瘤很常见，所有接受突变特征分析评估的此类肿瘤均有APOBEC特征。APOBEC特征和高肿瘤突变负荷预示着从诊断开始总生存期改善，且两项分析均预测化疗治疗结果较差。
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