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Abstract：
BACKGROUND: Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise, but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people.
OBJECTIVE: To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans.
METHODS: RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics, and outcome data were obtained from medical records.
RESULTS: Twenty-nine tumors were classified as luminal and 27 tumors as basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68-582.38, P = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 -0.37, P = 0.002), non-immune infiltrative signatures, and less advanced clinical stage.
CONCLUSIONS: Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype.
OBJECTIVE: To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans.
METHODS: RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics, and outcome data were obtained from medical records.
RESULTS: Twenty-nine tumors were classified as luminal and 27 tumors as basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68-582.38, P = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 -0.37, P = 0.002), non-immune infiltrative signatures, and less advanced clinical stage.
CONCLUSIONS: Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype.
摘要：
背景：浸润性尿路上皮癌（InvUC）患者需要改进的治疗方法。针对分子亚型的定制治疗有望实现，但需要进一步研究，包括临床前动物模型的研究。自然发生的犬InvUC具有腔和基底亚型，模仿那些在人类身上观察到的，并且可以为人类的疾病提供相关的模型。
目的：为了进一步验证犬InvUC模型，确定了与犬的腔和基底亚型相关的临床和肿瘤特征，与人类的发现相比。
方法:对来自四只正常狗的56只犬InvUC组织和膀胱粘膜进行RNA测序(RNA-seq)分析。将数据与CanFam3.1比对,并鉴定差异表达的基因。用定义腔和基底亚型的基因组询问数据，免疫特征，和其他肿瘤特征。受试者和肿瘤特征，结果数据来自医疗记录.
结果：29个肿瘤被分类为管腔肿瘤，27个肿瘤被分类为基底亚型。在RNA-seq分析中，基底肿瘤与免疫浸润（OR52.22，95CI4.68-582.38，P=0.001）和癌症进展特征密切相关，更高级的临床阶段，探索性分析中远处转移的早期发作(P=0.0113)。管腔肿瘤与InvUC高危品种密切相关(OR0.06,95CI0.01-0.37,P=0.002),非免疫浸润特征，和不那么先进的临床阶段。
结论：患有InvUC的狗可以为在分子亚型和免疫状态的背景下测试新的治疗策略提供有价值的模型，以及寻找影响InvUC发病和亚型的种系变异。
目的：为了进一步验证犬InvUC模型，确定了与犬的腔和基底亚型相关的临床和肿瘤特征，与人类的发现相比。
方法:对来自四只正常狗的56只犬InvUC组织和膀胱粘膜进行RNA测序(RNA-seq)分析。将数据与CanFam3.1比对,并鉴定差异表达的基因。用定义腔和基底亚型的基因组询问数据，免疫特征，和其他肿瘤特征。受试者和肿瘤特征，结果数据来自医疗记录.
结果：29个肿瘤被分类为管腔肿瘤，27个肿瘤被分类为基底亚型。在RNA-seq分析中，基底肿瘤与免疫浸润（OR52.22，95CI4.68-582.38，P=0.001）和癌症进展特征密切相关，更高级的临床阶段，探索性分析中远处转移的早期发作(P=0.0113)。管腔肿瘤与InvUC高危品种密切相关(OR0.06,95CI0.01-0.37,P=0.002),非免疫浸润特征，和不那么先进的临床阶段。
结论：患有InvUC的狗可以为在分子亚型和免疫状态的背景下测试新的治疗策略提供有价值的模型，以及寻找影响InvUC发病和亚型的种系变异。
