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PTPN11 mutations in canine and human disseminated histiocytic sarcoma
Author(s) -
Hédan Benoit,
Rault Mélanie,
Abadie Jérôme,
Ulvé Ronan,
Botherel Nadine,
Devauchelle Patrick,
CopieBergman Christiane,
Cadieu Edouard,
Parrens Marie,
Alten Julia,
Zalcman Emmanuelle L.,
Cario Gunnar,
Damaj Gandhi,
Mokhtari Karima,
Le Loarer Francois,
CoulombLhermine Aurore,
Derrien Thomas,
Hitte Christophe,
Bachelot Laura,
Breen Matthew,
Gilot David,
Blay Jean Y.,
Donadieu Jean,
André Catherine
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32991
Subject(s) - ptpn11 , kras , histiocytic sarcoma , cancer research , histiocyte , biology , mapk/erk pathway , cancer , mutation , medicine , pathology , immunology , kinase , genetics , gene
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.