Activating Mutations inandin Canine Histiocytic Sarcomas.

Abstract

While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in thegene (E76K). We have now identified a second missense mutation in PTPN11 (G503V), and a mutation in KRAS (Q61H) present in HS cell lines. These mutations are associated with malignancies in humans, and known to be gain-of-function mutations that result in activation of the mitogen-activated protein kinase (MAPK) pathway. The goal of the present study was to evaluate the prevalence of these mutations in a large sample of HS cases from BMDs and golden retrievers, and in lymphoma cases, from a cohort of BMDs. Mutations inwere present in HS in 41/96 (43%) BMDs, and in 3/13 (23%) golden retrievers. PTPN11 mutations E76K and G503V did not coexist in the same neoplasm. Themutation was much less frequent, with a prevalence of 3.1% (3/96). We did not identify eithernormutations in any of the lymphoma samples. These results point out the potential relevance ofandmutations as activators of the oncogenic MAPK pathway for canine HS, particularly in BMDs.