APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer.
APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer.
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DOI：
10.3389/fonc.2022.816706
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发表时间：
2022
影响因子：
4.7
通讯作者：
Koshkin VS
中科院分区：
文献类型：
--
作者：
Natesan D;Zhang L;Martell HJ;Jindal T;Devine P;Stohr B;Espinosa-Mendez C;Grenert J;Van Ziffle J;Joseph N;Umetsu S;Onodera C;Turski M;Chan E;Desai A;Aggarwal R;Wong A;Porten S;Chou J;Friedlander T;Fong L;Small EJ;Sweet-Cordero A;Koshkin VS
肿瘤突变负荷 (TMB) 和 APOBEC 突变特征是晚期尿路上皮癌 (aUC) 患者的潜在预后标志物。它们在预测 aUC 特定治疗结果方面的效用值得进一步研究。我们回顾性回顾了用 UCSF500 评估的连续 UC 病例，UCSF500 是一种机构检测，使用目标 DNA 的混合捕获富集来询问 479 个常见癌症基因。超突变肿瘤 (HM) 定义为 TMB ≥10 个突变/Mb，也评估了 APOBEC 突变特征，而非 HM (NHM) 肿瘤由于 TMB 较低而未进行评估。对数秩检验用于确定感兴趣的患者组之间的总生存期 (OS) 和无进展生存期 (PFS) 是否存在差异。在进行 UCSF500 检测的 75 名 aUC 患者中，46 名患者可评估 TMB，其中 19 名患者（41%）患有 HM 肿瘤，其余患有 NHM 肿瘤（27 名患者）。另外 29 名患者的 TMB 状态未知。在 19 名 HM 患者中，所有 16 名可评估进行分析的患者均具有 APOBEC 特征。 HM 患者 (N=19) 与 NHM 患者 (N=27) 相比，诊断后 OS 有所改善（125.3 个月 vs 35.7 个月，p=0.06），但接受化疗的患者 OS 较差（7.0 个月 vs 13.1 个月，p=0.04）。将 APOBEC 患者 (N=16) 与其余 56 名患者（包括 27 名 NHM 患者和 29 名 TMB 未知患者）进行比较，显示 APOBEC 患者自诊断起 OS 有所改善（125.3 个月 vs 44.5 个月，p=0.05），但接受化疗的患者 OS 较差（7.0 个月 vs 13.1 个月，p=0.05）。 APOBEC 和 HM 状态均与免疫治疗的反应无关。在使用 UCSF500（机构 NGS 小组）评估的大型单机构 aUC 队列中，HM 肿瘤很常见，并且评估突变特征分析的所有此类肿瘤都具有 APOBEC 特征。 APOBEC 特征和高 TMB 是诊断后 OS 改善的预后，这两项分析还预测化疗治疗的较差结果。
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. 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. 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 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. 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.
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影响因子：
--
作者：
Glaser AP;Fantini D;Wang Y;Yu Y;Rimar KJ;Podojil JR;Miller SD;Meeks JJ
通讯作者：
Meeks JJ
影响因子：
4.6
作者：
Mullane SA;Werner L;Rosenberg J;Signoretti S;Callea M;Choueiri TK;Freeman GJ;Bellmunt J
通讯作者：
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作者：
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通讯作者：
Rozen SG
影响因子：
16
作者：
Harris, RS;Petersen-Mahrt, SK;Neuberger, MS
通讯作者：
Neuberger, MS
影响因子：
--
作者：
Swami, Umang;Grivas, Petros;Agarwal, Neeraj
通讯作者：
Agarwal, Neeraj