Risk Factors Associated with Development of Histiocytic Sarcoma in Bernese Mountain Dogs

Abstract

BackgroundHistiocytic sarcoma (HS) is a rare but aggressive malignancy in humans that is poorly responsive to existing treatments. Although rare in most breeds of dogs, HS is common in Bernese mountain dogs (BMDs).ObjectiveDetermine risk factors associated with development of HS in BMD.AnimalsA total of 216 BMD were registered with the Berner‐Garde Foundation.MethodsAn internet‐based cross‐sectional survey was used to collect information from owners of BMD diagnosed with HS and owners of disease‐free littermates of dogs with HS. Mixed‐effects logistic regression (MELR) and conditional logistic regression (CLR) were used in parallel to examine associations between potential risk factors and the occurrence of HS.ResultsWhen controlling for litter as a marker of relatedness, dogs diagnosed with orthopedic conditions were found to be more likely to develop HS (MELR, OR: 2.5, 95% CI: 1.5, 5.2; CLR, OR: 2.81, 95% CI: 1.1, 7.3), whereas dogs receiving prescription anti‐inflammatory medications were found to be at considerably lower risk of developing HS (MELR, OR: 0.42, 95% CI: 0.2, 0.8; CLR, OR: 0.32, 95% CI: 0.1, 0.8).Conclusions and Clinical ImportanceThese results suggest inflammation may be a modifiable risk factor for the development of HS in BMD.

Prior joint disease is associated with increased risk of periarticular histiocytic sarcoma in dogs

“…Dogs in this study with PAHS were more likely to have had prior joint disease in their tumour‐affected joint when compared with the control population. The OR of 13.42 (95% CI: 4.33‐48.63, P < .0001) suggests there is a strong relationship between joint disease and development of PAHS; the existence of this association has been demonstrated previously in Bernese Mountain Dogs and this study confirms that the relationship exists in dogs of other breeds as well. Not all of the breeds reported in the current study have been previously suggested to be predisposed to HS.…”

“…Inflammation could therefore predispose to both cruciate rupture and PAHS. A recent report by Ruple et al demonstrated Bernese Mountain Dogs receiving prescription anti‐inflammatory medications had a lower risk of HS development, suggesting that inflammation may play a role in HS development in this breed . How the known genetic risk for HS in the Bernese Mountain Dog impacts the effect of inflammation in promoting HS development is not yet known.…”

“…Dogs with prior orthopaedic disease were 2.5 times more likely to develop HS than those without. Interestingly, dogs in the same study treated with prescription anti‐inflammatory medications were at a lower risk for development of HS . In another study, Bernese Mountain Dogs were found to be 5.4 times more likely to develop PAHS in a previously diseased joint compared with a healthy joint .…”

“…Breed predispositions to HS have been reported in the Bernese Mountain Dog, Flat Coated Retriever and Rottweiler and there is an inherited risk in Bernese Mountain Dogs, suggesting the possibility of genetic risk factors. Other investigated potential risk factors for HS in dogs include environmental exposures, previous medical history and prior orthopaedic disease . In a retrospective study of Bernese Mountain Dogs, orthopaedic disease was determined to be a predisposing factor associated with the development of HS.…”

The tree that hides the forest: identification of common predisposing loci in several hematopoietic cancers and several dog breeds

“…Indeed HS predisposed breeds, especially BMD, are also predisposed to reactive histiocytic diseases 41 but also to other immune or inflammatory diseases such as glomerulonephritis, aseptic meningitis or inflammatory bowel disease (https://www.bmdca.org/health/diseases.php) 42,43 . While no causal relationship was proved between inflammation and HS, inflammation is suspected to contribute to HS development [44][45][46] . In these conditions it is not surprising that HS GWAS hits overlap not only candidate tumor suppressor genes (TUSC1) or well-known tumor suppressors involved in cell cycle (CDKN2A), in genome stability (telomere protection: POT1, replication stress/DNA damage: FHIT…) but also in inflammation (IL17a, IL17rd, SPNS3, ARHGEF3…) (Supplementary Table 7).…”