Invasive urothelial carcinoma (iUC) is highly similar between dogs and humans in terms of pathologic presentation, molecular subtypes, response to treatment and age at onset. Thus, the dog is an established and relevant model for testing and development of targeted drugs benefiting both canine and human patients. We sought to identify gene expression patterns associated with two primary types of canine iUC tumors: those that express a common somatic mutation in the BRAF gene, and those that do not. We performed RNAseq on tumor and normal tissues from pet dogs. Analysis of differential expression and clustering, and positional and individual expression was used to develop gene set enrichment profiles distinguishing iUC tumors with and without BRAFV595E mutations, as well as genomic regions harboring excessive numbers of dysregulated genes. We identified two expression clusters that are defined by the presence/absence of a BRAFV595E (BRAFV600E in humans) somatic mutation. BRAFV595E tumors shared significantly more dysregulated genes than BRAF wild-type tumors, and vice versa, with 398 genes differentiating the two clusters. Key genes fall into clades of limited function: tissue development, cell cycle regulation, immune response, and membrane transport. The genomic site with highest number of dysregulated genes overall lies in a locus corresponding to human chromosome 8q24, a region frequently amplified in human urothelial cancers. These data identify critical sets of genes that are differently regulated in association with an activating mutation in the MAPK/ERK pathway in canine iUC tumors. The experiments also highlight the value of the canine system in identifying expression patterns associated with a common, shared cancer.

中文翻译：

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犬浸润性尿路上皮癌的 RNAseq 表达模式揭示了两个不同的肿瘤簇以及与人类膀胱肿瘤共同的失调区域


狗和人类的浸润性尿路上皮癌（iUC）在病理表现、分子亚型、治疗反应和发病年龄方面高度相似。因此，狗是测试和开发靶向药物的既定且相关的模型，使犬类和人类患者受益。我们试图确定与两种主要类型的犬 iUC 肿瘤相关的基因表达模式：表达 BRAF 基因常见体细胞突变的肿瘤和不表达常见体细胞突变的肿瘤。我们对宠物狗的肿瘤和正常组织进行了 RNAseq。使用差异表达和聚类、位置和个体表达的分析来开发基因集富集图谱，以区分具有和不具有 BRAFV595E 突变的 iUC 肿瘤，以及含有过多失调基因的基因组区域。我们确定了两个表达簇，它们由 BRAFV595E（人类中的 BRAFV600E）体细​​胞突变的存在/不存在来定义。 BRAFV595E 肿瘤比 BRAF 野生型肿瘤共享更多失调基因，反之亦然，有 398 个基因区分这两个簇。关键基因属于功能有限的进化枝：组织发育、细胞周期调节、免疫反应和膜运输。失调基因数量最多的基因组位点总体位于与人类染色体 8q24 相对应的基因座，该区域在人类尿路上皮癌中经常扩增。这些数据确定了与犬 iUC 肿瘤中 MAPK/ERK 通路激活突变相关的不同调控的关键基因组。这些实验还强调了犬类系统在识别与常见癌症相关的表达模式方面的价值。