Gain‐of‐function mutation in PTPN11 in histiocytic sarcomas of Bernese Mountain Dogs

Abstract

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm of dendritic cell origin that is common in certain breeds of dogs. High prevalence of fatal, disseminated HS has been described in Bernese Mountain Dogs (BMDs). Support for genetic predisposition to develop HS has been presented in several studies, but to date, causative genetic events have not been reported. In addition, no driver mutations have been identified in tumours. Recently, E76K gain-of-function mutation in SHP2 encoded by the PTPN11 gene has been described in human histiocytic malignancies. In our study, we identified the PTPN11 in HS of BMDs. Amplification of exon 3 of the PTPN11 gene followed by Sanger sequencing was used to detect the mutation and estimate the prevalence in HS from 30 BMDs, 13 Golden Retrievers and 10 other dog breeds. The overall prevalence of PTPN11 in HS of BMDs was 36.67% compared with 8.69% in other breeds. No mutation was identified in normal tissues from 10 BMDs with HS that carried the mutation and 12 control dogs with no neoplastic disease, including 6 BMDs. Increased immunoreactivity for AKT, phosphorylated ERK1/2 and phosphorylated AKT in a small subset of BMDs with PTPN11 suggests that a gain-of-function might be mediated by the ERK and AKT pathways. These data suggest PTPN11 as an important driver mutation of HS in BMDs. This information may not only aid in unravelling the tumourigenic events associated with HS in BMDs, but also help in identifying more promising therapeutic strategies.

Targeting MEK in a Translational Model of Histiocytic Sarcoma

“…As recently reported by our group, a gain-of-function mutation in PTPN11 was found to be associated with HS in BMDs (37). Activating mutations in the PTPN11 gene have also been reported in human HS cases (15,18,60,61).…”

“…As in humans, the MAPK pathway seems to contribute to HS in dogs, as exemplified through a gain-of-function mutation PTPN11 E76K , a gene that encodes SHP2, required for MAPK. This mutation was recently reported in canine HS by our group and found to be prevalent in BMDs compared with other breeds (37% vs. 9%) (37).…”

Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

“…It has been shown that dogs with lymphoid neoplasia and mammary carcinoma had a higher amount of cfDNA in plasma than controls 19,20 , although this increase is not specific to cancer. Over the last 10 years, recurrent somatic alterations have been described in several canine cancers such as multicentric lymphoma 21,22 , histiocytic sarcoma (HS) [23][24][25][26][27] and oral malignant melanoma (OMM) [28][29][30][31][32] . Detection of such cancer-specific recurrent somatic alterations in ctDNA may allow to develop new minimally invasive biomarkers for diagnosis, prognosis and to assess treatment-response in veterinary medicine.…”

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

“…The clinical presentation, histopathology and issue of this canine cancer are similar to those observed in humans 22,23 . These breed predispositions allowed the collection of numerous samples to successfully identify somatic variants of the MAPK pathway 24,25 and we recently showed that the same mutations of PTPN11, the most frequently altered gene of the MAPK pathway, are found in human and canine HS 25 . But most importantly, these breed predispositions to specific clinical presentations allow to unravel the genetic bases of HS.…”