Dog breeds provide unique genetic pools for studying rare disorders that affect both dogs and humans. Understanding the prevalence of these disorders is a key first step in addressing breed-associated diseases and establishing the utility of the dog as a spontaneous model of human disease. Analysis of the community-based assessment of health status of Bernese mountain dogs (BMD) was conducted utilizing an open-access database, the Berner-Garde Database. The Berner-Garde Database was accessed on March 1, 2013 and outputted to SQL, a database management system, for querying. Complete entries that included sex, age, and diagnosis were chosen, resulting in 7,262 individual dogs for analysis. Nearly 86% of these dogs died by ten years of age. Over 44% of diagnoses were categorized as cancer; the most prevalent cancer was histiocytic sarcoma, which comprised 37% of the cancer diagnoses, while lymphoma was the second highest cancer diagnosis at 20%. During the last twenty years cancer has surpassed dysplasias as the most important diagnosis for BMDs. The prevalence of histiocytic sarcoma diagnoses has grown, which may be partially due to improved diagnostic criteria. At the same time, the median age at death for BMDs with histiocytic sarcoma has not improved, but in fact, has decreased over the last decade. Despite improvement in diagnosis of histiocytic sarcoma, improvements in treatment of this disease have not followed.;Histiocytic diseases encompass a spectrum of proliferative diseases in dogs and humans. Human histiocytic diseases are rare diseases that affect children and adults, but in BMDs, these diseases are common. Canine histiocytic diseases range from benign histiocytoma to malignant histiocytic sarcoma (HS), which in the disseminated form has a poor prognosis and does not respond well to chemotherapeutics. The goal of this work is to unravel the mechanisms of tumorigenesis in canine histiocytic diseases by probing the differential expression of microRNAs (miRNA) along the spectrum of canine histiocytic diseases. As regulators of gene expression, miRNAs will provide insight into the pathways for tumorigenesis in histiocytic malignancies as compared to benign histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, histiocytic sarcoma, and hemophagocytic histiocytic sarcoma. These samples were compared to normal canine histiocytes derived from peripheral blood and peritoneal fluid. Analysis of the profiling data yielded several miRNAs, which were selected for validation by quantitative reverse transcription PCR (qRT-PCR). Data analysis with unsupervised clustering revealed sets of miRNAs that were overexpressed in BMDs or mixed breed dogs. Validation by qRT-PCR showed significant upregulation of miR-125b and miR-152 in dogs affected with a histiocytic disease. MiRNAs that are critical for tumorigenesis represent targets for manipulation to increase our understanding of these malignancies and discover novel and effective therapies.;As part of a concurrent approach to understanding histiocytic disease, the whole genome of a female spayed BMD with histiocytic sarcoma was sequenced using three genomic DNA samples. The first was a blood sample taken from this dog when she was 4 years of age, prior to diagnosis with histiocytic sarcoma. The second was a sample of a mediastinal tumor mass and the third sample was a cell line derived from an affected abdominal lymph node; both of these samples were taken at necropsy. There were 29 spontaneous nonsynonymous mutations in the tumor that were predicted to be deleterious and four of these variants were in genes associated with cancer including SSH3,ITGB7, and FANCM. Six mutations potentially represented loss of heterozygosity including FAT1, MTUS1, and LRP1B, which are associated with cancer. Over one hundred variants were considered germ line mutations, the majority of which were heterozygous in all the samples and fifty-one were homozygous in all three samples. Using these data, future work will involve evaluating the genes in independent affected and unaffected BMDs to validate the variants as potential driver mutations of histiocytic sarcoma tumorigenesis.
展开▼
