跨物种肿瘤基因组学为人类肌层侵袭性膀胱癌提供了洞察力。
Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer.
发表日期：2023 Aug 28
作者：
Kim Wong, Federico Abascal, Latasha Ludwig, Heike Aupperle-Lellbach, Julia Grassinger, Colin W Wright, Simon J Allison, Emma Pinder, Roger M Phillips, Laura P Romero, Arnon Gal, Patrick J Roady, Isabel Pires, Franco Guscetti, John S Munday, Maria C Peleteiro, Carlos A Pinto, Tânia Carvalho, João Cota, Elizabeth C Du Plessis, Fernando Constantino-Casas, Stephanie Plog, Lars Moe, Simone de Brot, Ingrid Bemelmans, Renée Laufer Amorim, Smitha R Georgy, Justina Prada, Jorge Del Pozo, Marianne Heimann, Louisiane de Carvalho Nunes, Outi Simola, Paolo Pazzi, Johan Steyl, Rodrigo Ubukata, Peter Vajdovich, Simon L Priestnall, Alejandro Suárez-Bonnet, Franco Roperto, Francesca Millanta, Chiara Palmieri, Ana L Ortiz, Claudio S L Barros, Aldo Gava, Minna E Söderström, Marie O'Donnell, Robert Klopfleisch, Andrea Manrique-Rincón, Inigo Martincorena, Ingrid Ferreira, Mark J Arends, Geoffrey A Wood, David J Adams, Louise van der Weyden
来源：
Genome biology
摘要：
在人类中，肌层浸润性膀胱癌(MIBC)具有高度侵袭性且与预后不良相关。高突变负荷和大量改变基因的情况下，有必要策略性地区分关键驱动事件。狗和猫患上的尿路上皮癌(UC)在组织学和临床上与人类的MIBC相似。以水龙骨为食物的牛也患上UC，这与暴露于致癌物质ptaquiloside有关。这些物种可能代表自发和致癌物质诱导的UC的相关动物模型，可以揭示人类MIBC的见解。对国内犬(数量n = 87)和猫(数量n = 23) UC的全外显子测序，并与人类MIBC进行比较分析，发现动物病例的突变率较低，APOBEC突变特征不存在。发现了驱动基因的汇聚(ARID1A, KDM6A, TP53, FAT1和NRAS)，以及涉及细胞周期和染色质重塑调控的常见局部扩增和缺失基因。我们确定了犬和猫子UC中的一部分存在错配修复缺陷，MSH2双等位基因失活。牛UC(数量n = 8)明显不同；我们在其中发现了新颖的突变特征，在体外实验中，这些特征在使用水龙骨提取物或纯化的ptaquiloside处理的人类膀胱癌细胞中得到重现。犬和猫尿路上皮UC代表了人类MIBC的相关模型，并通过跨物种分析可以发现进化保守的驱动基因。我们表征了与水龙骨和ptaquiloside暴露相关的牛UC中的突变特征，这是与人类相关的癌症暴露。我们的研究证明了跨物种比较分析在理解人类和动物UC方面的相关性。© 2023. BioMed Central Ltd., part of Springer Nature.
In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC.Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside.Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.© 2023. BioMed Central Ltd., part of Springer Nature.