野火理论的特点是受到突变克隆影响的正常组织区域。膀胱野火理论可能解释了膀胱癌的发展和复发，并可能与治疗结果相关。为了研究野火理论在高危非肌层浸润性膀胱癌（NMIBC）患者接受卡介苗（BCG）治疗中的预测和预后作用，我们对136名NMIBC患者的751个膀胱活检和234个尿液样本进行全面的基因组和蛋白质组分析。样本在疾病过程中的多个时间点被收集。通过深度定向测序和纠错模型，测量了在外观正常的膀胱活检中的野火理论水平。终点事件包括复发率和进展率。使用Cox回归分析、Wilcoxon秩和Fisher的确切检验。高水平的野火理论与高肿瘤突变负荷（p = 0.007）、高肿瘤新抗原负荷（p = 0.029）和高肿瘤相关CD8 T细胞耗竭（p = 0.017）相关。此外，高野火理论与较差的短期结果（p = 0.029）相关。在膀胱癌相关基因（如KDM6A、ARID1A和TP53）的非同义突变已在外观正常的膀胱活检中被确定为早期疾病驱动基因。尿液肿瘤DNA（utDNA）水平反映了膀胱肿瘤负担，并源自肿瘤和野火理论。BCG后高水平的utDNA与较差的临床结果（p = 0.027）和疾病进展（p = 0.003）相关。高野火理论导致尿液中与血管生成和增殖相关的蛋白质水平升高。限制包括活检数量和时间点分析的变异。野火理论水平与肿瘤发展、免疫反应和临床结果相关。utDNA测量可用于监测疾病状况和治疗反应。膀胱内衬组织的分子变化导致肿瘤复发。尿液测量可用于监测膀胱癌的状况和治疗反应。版权所有©2023年作者。由Elsevier B.V.出版。保留所有权利。

Field cancerization is characterized by areas of normal tissue affected by mutated clones. Bladder field cancerization may explain the development and recurrence of bladder cancer and may be associated with treatment outcomes.To investigate the predictive and prognostic roles of field cancerization in patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with bacillus Calmette-Guérin (BCG).We conducted comprehensive genomic and proteomic analyses for 751 bladder biopsies and 234 urine samples from 136 patients with NMIBC. The samples were collected at multiple time points during the disease course. Field cancerization in normal-appearing bladder biopsies was measured using deep-targeted sequencing and error correction models.Endpoints included the rates of recurrence and progression. Cox regression and Wilcoxon rank-sum and Fisher's exact tests were used.A high level of field cancerization was associated with high tumor mutational burden (p = 0.007), high tumor neoantigen load (p = 0.029), and high tumor-associated CD8 T-cell exhaustion (p = 0.017). In addition, high field cancerization was associated with worse short-term outcomes (p = 0.029). Nonsynonymous mutations in bladder cancer-associated genes such as KDM6A, ARID1A, and TP53 were identified as early disease drivers already found in normal-appearing bladder biopsies. Urinary tumor DNA (utDNA) levels reflected the bladder tumor burden and originated from tumors and field cancerization. High levels of utDNA after BCG were associated with worse clinical outcomes (p = 0.027) and with disease progression (p = 0.003). High field cancerization resulted in high urinary levels of proteins associated with angiogenesis and proliferation. Limitations include variation in the number of biopsies and time points analyzed.Field cancerization levels are associated with tumor development, immune responses, and clinical outcomes. utDNA measurements can be used to monitor disease status and treatment response.Molecular changes in the tissue lining the bladder result in tumor recurrence. Urinary measurements may be used to monitor bladder cancer status and treatment responses.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.