Introduction

Histiocytic sarcoma (HS) is a rare but devastating cancer in predisposed breeds: Bernese Mountain dogs (BMD), Rottweilers and flat coated retriever (FCR). Since there is no available efficient treatment, a better understanding of the genetic mechanisms leading to HS is needed to improve treatment of affected dogs.

Material and Methods

Genotyping was performed on 455 HS cases and 408 unaffected BMDs, Rottweilers and FCRs using the available SNP chips (Illumina 22K, 170K and Affymetrix 712K, SNP arrays). The Beagle software was used to impute the Illumina SNP arrays to the Affymetrix 712K SNP array. Three loci were captured and sequenced on 16 dogs with the SureSelect Target enrichment system. RNA-Seq was performed on 4 HS tumors and identified mutations were validated by Sanger sequencing of 100 canine HS cases. Seven in-house cell lines were developed to explore the main altered pathways.

Results

Genome-Wide Association studies on a large cohort of HS predisposed breeds confirmed the major role of CFA11 locus in HS predisposition (Shearin et al. 2012). The multi-breed approach not only refined the CFA11 locus to only 200 kb, but also allowed to identify other predisposing loci to several hematopoietic cancers. Bioinformatic analyses on three main loci are ongoing on 16 dogs. Based on these results, we developed a genetic risk test and the follow up of >3000 BMDs tested over the 8 years-used has already showed the benefice of this genetic risk test to improve BMDs health. In parallel, we identified somatic recurrent mutations in 53% in a specific pathway and showed a link with the disseminated HS form (p value=8.26x10-7 Chi-square test). We then demonstrated the sensitivity of HS cell lines to available drugs targeting this pathway.

All together, these genetic results provide a better understanding of the genetics and treatment of HS in dogs.