自然发生的犬浸润性泌尿癌（iUC）在组织病理学、转移、治疗反应和低存活率方面与人类肌肉浸润性膀胱癌非常相似。该疾病的异质性导致人类中存在大量风险位点，但大多数影响很小。需要新的、准确的侵袭性膀胱癌动物模型。在狗中，不同品种的 iUC 发生率明显不同，从而提供了识别其他危险因素并克服人类绘图研究中遇到的基因座异质性的机会。在此介绍的关联研究中，包括 100 只喜乐蒂牧羊犬和 58 只其他品种的狗，我们在 NIPAL1 基因内发现了一个纯合蛋白改变点突变，该突变使风险增加八倍 (OR = 8.42，CI = 3.12-22.71)，约占喜乐蒂牧羊犬 IUC 风险的 30%。六个额外基因座的纳入解释了该品种的大部分疾病风险，并解释了本研究中近 75% 的表型。与肿瘤的序列数据相结合，我们发现 MAPK 信号通路的变异是狗 iUC 易感性的首要原因。© 2024。这是美国政府的作品，在美国不受版权保护；可能适用外国版权保护。

Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12-22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs.© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.