Pathogenetic studies of sarcoma development in retriever breeds

Abstract

In the Dutch population of Golden retrievers, a predisposition for the development of cancer in general and certain types of cancer (such as mast cell tumours and possibly also soft tissue sarcomas (STS)) was shown to exist. In addition, age, location and incidence of various tumours differed as related to the diagnostical procedure of choice, being either cytology or histology, indicating a selection bias for diagnostic procedure. A subset of the collected cohort, consisting of unclassified sarcomas, (n=110) were selected for revision. Revision was based on morphological characteristics and, if deemed necessary, additional immunohistochemistry. In 58 tumours, we were able to arrive at the diagnosis of a specific STS. As many as 31 tumours (28%), however, were on revision not considered to be STS. Four neoplasms (4%) were considered non-neoplastic. These numbers illustrate the necessity for revision (and \ possibly subclassification) of this group of tumours.

DNA-aneuploidy may reflect a malignant nature of mesenchymal proliferations and herald gross genomic instability. Of all mesenchymal tumours examined within this study, half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploidy, and all of the inflammatory lesions were diploid. The determination of DNA ploidy status is considered to be of additional value when attempting to better differentiate between malignant and non-malignant mesenchymal lesions. In addition, hypoploidy appears more common in canine sarcomas and hyperploid cases show less deviation of the DNA index than human sarcomas. This strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development.

Aiming to identify genes causing the suspected breed predispositionfor the development of STS in both the Labrador- and Golden retriever breed,a genome-wide association study was performed. Results were suggestive for a germ-line genetic connection between the development of STS in the Labrador- and Golden retriever breed. Within both breeds, different loci (all of which contained candidate genes already known to be involved in the development of cancer) could be identified. The histiocytic sarcoma is a specific sarcoma subtype that often develops in Flatcoated retrievers. Within this tumour, the significantly altered expression of nine genes and deregulation of gene signaling pathways were identified by means of a microarray study and additional q PCR confirmation. These genes were not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Histiocytic sarcomas can be grouped mainly into a soft tissue- and visceral form. The Flatcoated retriever is predisposed mainly for the first subtype. Genetic differences possibly causing the phenotypical variation of these two histiocytic sarcoma subtypes were identified by microarray analyses. The significantly aberrant expression of three genes were confirmed by q PCR. These differences indicate that these two forms of histiocytic sarcoma in the dog display a variation in gene expression.