Canine histiocytic malignancies (HM) are rare across the general dog population, but overrepresented in certain breeds, such as Bernese mountain dog and flat-coated retriever. Accurate diagnosis relies on immunohistochemical staining to rule out histologically similar cancers with different prognoses and treatment strategies (e.g., lymphoma and hemangiosarcoma). HM are generally treatment refractory with overall survival of less than 6 months. A lack of understanding regarding the mechanisms of disease development and progression hinders development of novel therapeutics. While the study of human tumors can benefit veterinary medicine, the rarity of the suggested orthologous disease (dendritic cell sarcoma) precludes this. This study aims to improve the understanding of underlying disease mechanisms using genome-wide DNA copy number and gene expression analysis of spontaneous HM across several dog breeds. Extensive DNA copy number disruption was evident, with losses of segments of chromosomes 16 and 31 detected in 93% and 72% of tumors, respectively. Droplet digital PCR (ddPCR) evaluation of these regions in numerous cancer specimens effectively discriminated HM from other common round cell tumors, including lymphoma and hemangiosarcoma, resulting in a novel, rapid diagnostic aid for veterinary medicine. Transcriptional analysis demonstrated disruption of the spindle assembly complex, which is linked to genomic instability and reduced therapeutic impact in humans. A key signature detected was up-regulation of Matrix Metalloproteinase 9 (MMP9), supported by an immunohistochemistry-based assessment of MMP9 protein levels. Since MMP9 has been linked with rapid metastasis and tumor aggression in humans, the data in this study offer a possible mechanism of aggression in HM.

中文翻译：

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犬组织细胞恶性肿瘤的全基因组DNA拷贝数分析和靶向转录分析确定了诊断特征并突出了纺锤体组装复合物的破坏。

犬组织细胞恶性肿瘤（HM）在普通犬群中很少见，但在某些犬种中却过多，如伯恩山地犬和扁平犬。准确的诊断依靠免疫组织化学染色来排除具有不同预后和治疗策略（例如淋巴瘤和血管肉瘤）的组织学相似的癌症。HM通常是难治性治疗，总生存期不到6个月。对疾病发展和进展机制的缺乏了解阻碍了新疗法的发展。尽管对人类肿瘤的研究可以使兽医学受益，但建议的直系同源疾病（树突状细胞肉瘤）的罕见性阻止了这一点。这项研究的目的是通过使用全基因组DNA拷贝数和几种犬种自发性HM的基因表达分析来增进对潜在疾病机制的理解。DNA拷贝数的广泛破坏是显而易见的，分别在93％和72％的肿瘤中检测到16和31号染色体的片段丢失。液滴数字PCR（ddPCR）评估了许多癌症标本中的这些区域，从而有效地将HM与其他常见的圆形细胞肿瘤（包括淋巴瘤和血管肉瘤）区分开来，从而为兽医学提供了一种新颖，快速的诊断工具。转录分析表明，纺锤体组装复合物被破坏，这与基因组不稳定和对人类的治疗影响降低有关。检测到的关键特征是基质金属蛋白酶9（MMP9）的上调，通过基于免疫组织化学的MMP9蛋白水平评估得到支持。由于MMP9与人类的快速转移和肿瘤侵袭有关，因此本研究中的数据提供了HM侵袭的可能机制。