PTPN11 mutations in canine and human disseminated histiocytic sarcoma. Issue 6 (8th April 2020) - Hédan, Benoit
Abstract : In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS ( 7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti‐proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans. Abstract : What's new? Histiocytic sarcoma (HS) is a rare, aggressive, and heterogeneous cancer, which remains hard to treat. Here, the authors compare genetic alterations between human HS and spontaneously occurring canine HS as a way to home in on mutations important for cancer progression. They identified mutations in the MAPK pathway in a majority of cases, and in particular detected an association between mutations in the PTPN11 gene and one specific HS subtype in both species. They compared the effectiveness of MAP kinase inhibitors in 8 canine cell lines, demonstrating that targeting the MAPK pathway may effectively treat BRAF wild type HS.