Skip to Main content Skip to Navigation
Journal articles

PTPN11 mutations in canine and human disseminated histiocytic sarcoma

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.
Complete list of metadatas

Cited literature [27 references]  Display  Hide  Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-02534873
Contributor : Laurent Jonchère <>
Submitted on : Monday, April 27, 2020 - 10:46:57 AM
Last modification on : Friday, August 28, 2020 - 4:10:45 PM

File

Hédan et al-2020-PTPN11 mutat...
Files produced by the author(s)

Identifiers

Citation

Benoit Hedan, Mélanie Rault, Jérôme Abadie, Ronan Ulvé, Nadine Botherel, et al.. PTPN11 mutations in canine and human disseminated histiocytic sarcoma. International Journal of Cancer, Wiley, 2020, 147 (6), pp.1657-1665. ⟨10.1002/ijc.32991⟩. ⟨hal-02534873⟩

Share

Metrics

Record views

65

Files downloads

2