title: SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes.
abstract: Mastocytosis is a rare and chronic disease with phenotypes ranging from indolent to severe. Prognosis for this disease is variable and very few biomarkers to predict disease evolution or outcome are currently known. We have performed comprehensive screening in our large cohort of mastocytosis patients for mutations previously found in other myeloid diseases and that could serve as prognostic indicators. KIT, SRSF2-P95 and TET2 mutations were by far the most frequent, detected in 81%, 24% and 21% of patients, respectively. Where TET2 and SRSF2-P95 mutation both correlated with advanced disease phenotypes, SRSF2-P95 hotspot mutation was found almost exclusively in patients diagnosed with associated clonal hematologic non-mast cell disease. Statistically, TET2 and SRSF2-P95 mutations were highly associated, suggesting a mechanistic link between these two factors. Finally, analysis of both clonal and sorted cell populations from patients confirms the presence of these mutations in the mast cell component of the disease, suggests an ontological mutation hierarchy and provides evidence for the expansion of multiple clones. This highlights the prognostic potential of such approaches, if applied systematically, for delineating the roles of specific mutations in predisposing and/or driving distinct disease phenotypes.
authors.affiliation: erinn.soucie@inserm.fr.
authors.forename: Katia
authors.initials: K
authors.lastname: Hanssens
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brenet
authors.forename: Julie
authors.initials: J
authors.lastname: Agopian
authors.forename: Sophie
authors.initials: S
authors.lastname: Georgin-Lavialle
authors.forename: Gandhi
authors.initials: G
authors.lastname: Damaj
authors.forename: Laure
authors.initials: L
authors.lastname: Cabaret
authors.forename: Maria Olivia
authors.initials: MO
authors.lastname: Chandesris
authors.forename: Paulo
authors.initials: P
authors.lastname: de Sepulveda
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Erinn
authors.initials: E
authors.lastname: Soucie
mesh_terms: D060965:Clonal Evolution / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D008415:Mastocytosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human; D019009:Proto-Oncogene Proteins c-kit