肿瘤发病机制中，尤其是那些位于长链非编码RNA（lncRNA）功能区的癌相关变异的鉴定已成为重要任务。然而，尚不清楚参与膀胱癌易感性的lncRNA变异的遗传功能。在此，发现中国人群（3603例案例和4986例对照）中lncRNA膀胱癌细胞胞质富集转录本4（BCCE4）的microRNA反应元件（MREs）的rs62483508 G > A变异与降低膀胱癌风险显著相关（奇比值比=0.84，P=7.33×10-8），但在欧洲人群中未发现相关性。rs62483508 A等位基因的保护遗传效应发现在吸烟者或与香烟烟雾相关的致癌物4-氨基联苯胺（4-ABP）暴露中。随后的生物实验揭示rs62483508 A等位基因破坏了miR-328-3p与USP18结合亲和力，从而促进miRNA介导的USP18降解，从而特异性减弱下游PD-L1/PD-1相互作用。lncRNA BCCE4还富集于膀胱癌血浆、组织和细胞的外泌体中。这项综合研究阐明了lncRNA BCCE4在膀胱癌易感性中的遗传机制以及其在调控肿瘤发生中的免疫应答中的作用。这些发现提供了有价值的膀胱癌风险预测指标，有助于诊断和预防。© 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Identification of cancer-associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm-Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10-8 ) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke-related carcinogen 4-aminobiphenyl (4-ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR-328-3p to facilitate USP18 from miRNA-mediated degradation and thus specifically attenuates the downstream PD-L1/PD-1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.