Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA-seq) (19 patients), and single-cell RNA-seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t-tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5’-CTC-3’ and 5’-CTG-3’. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term ‘chemical carcinogenesis’. Transcriptomic analysis suggested high immune cell infiltration and luminal-like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC-derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen-related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen-related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland.

中文翻译：

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膀胱腺癌的突变特征和预后

膀胱腺癌是一种罕见的膀胱癌，由于缺乏分子特征，治疗选择有限。在这里，我们的目的是揭示膀胱腺癌的突变和转录组景观，并评估与预后的关系。2015年2月至2021年6月期间，共有23名膀胱腺癌患者入组。其中包括 16 名原发性膀胱腺癌患者和 7 名脐尿管腺癌患者。对样本进行了全外显子组测序（16 名患者）、全基因组测序（16 名患者）、批量 RNA 测序（RNA-seq）（19 名患者）和单细胞 RNA-seq（5 名患者）。还进行了相关分析、生存分析和t检验。在体细胞突变中观察到普遍的 T>A 取代，主要三核苷酸背景包括 5'-CTC-3' 和 5'-CTG-3'。这种模式主要是由与化学致癌物暴露（可能是马兜铃酸）相关的 COSMIC 特征 22 造成的，而这种情况在膀胱腺癌中尚未有报道。此外，拷贝数变化的基因也在KEGG术语“化学致癌”中富集。转录组分析表明大多数样本具有高免疫细胞浸润和管腔样特征。有趣的是，与仅具有化学致癌物相关特征的样本相比，一小部分具有 APOBEC 衍生突变特征的样本表现出更高的疾病进展风险，证实了膀胱腺癌的分子和预后异质性。这项研究展示了膀胱腺癌的突变和转录组学景观，并表明与膀胱腺癌中的 APOBEC 特征相比，化学致癌物相关的突变特征可能与更好的预后相关。© 2024 大不列颠及爱尔兰病理学会。