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.

中文翻译：

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自然发生的犬尿路上皮癌的基底和管腔分子亚型与肿瘤免疫特征和犬种有关

摘要

背景：

浸润性尿路上皮癌 (InvUC) 患者需要改进的治疗方法。针对分子亚型进行定制治疗很有希望，但需要进一步研究，包括在临床前动物模型中进行研究。自然发生的犬 InvUC 具有 luminal 和 basal 亚型，模仿在人类中观察到的亚型，并且可以为人类疾病提供相关模型。

客观的：

为了进一步验证犬 InvUC 模型，确定了与狗的管腔和基底亚型相关的临床和肿瘤特征，并与人类的发现进行了比较。

方法：

对来自四只正常犬的 56 份犬 InvUC 组织和膀胱粘膜进行了 RNA 测序 (RNA-seq) 分析。数据与 CanFam 3.1 对齐，并确定了差异表达的基因。使用定义管腔和基底亚型、免疫特征和其他肿瘤特征的基因组询问数据。从医疗记录中获得受试者和肿瘤特征以及结果数据。

结果：

29 个肿瘤被归类为管腔亚型，27 个肿瘤被归类为基底亚型。基底肿瘤与 RNA-seq 分析中的免疫浸润（OR 52.22，95%CI 4.68–582.38，P = 0.001）和癌症进展特征、更晚期的临床分期和探索性分析中较早发生远处转移密切相关（P  = 0.0113）。管腔肿瘤与 InvUC 高风险品种（OR 0.06，95%CI 0.01 –0.37，P  = 0.002）、非免疫浸润特征和较不晚期临床分期密切相关。

结论：

患有 InvUC 的狗可以提供一个有价值的模型，用于在分子亚型和免疫状态的背景下测试新的治疗策略，以及寻找影响 InvUC 发病和亚型的种系变异。