title: Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase.
abstract: Myelofibrosis is a myeloproliferative neoplasm that occurs de novo (primary myelofibrosis) or results from the progression of polycythemia vera or essential thrombocytemia (hereafter designated as secondary myelofibrosis or post-polycythemia vera/ essential thrombocythemia myelofibrosis). To progress in the understanding of myelofibrosis and to find molecular prognostic markers we studied 104 samples of primary and secondary myelofibrosis at chronic (n=68) and acute phases (n=12) from 80 patients, by using array-comparative genomic hybridization and sequencing of 23 genes (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). We found copy number aberrations in 54% of samples, often involving genes with a known or potential role in leukemogenesis. We show that cases carrying a del(20q), del(17) or del(12p) evolve in acute myeloid leukemia (P=0.03). We found that 88% of the cases were mutated, mainly in signaling pathway (JAK2 69%, NF1 6%) and epigenetic genes (ASXL1 26%, TET2 14%, EZH2 8%). Overall survival was poor in patients with more than one mutation (P=0.001) and in patients with JAK2/ASXL1 mutations (P=0.02). Our study highlights the heterogeneity of myelofibrosis, and points to several interesting copy number aberrations and genes with diagnostic and prognostic impact.
authors.affiliation: muratia@ipc.unicancer.fr.
authors.forename: Mandy
authors.initials: M
authors.lastname: Brecqueville
authors.forename: Jérôme
authors.initials: J
authors.lastname: Rey
authors.forename: Raynier
authors.initials: R
authors.lastname: Devillier
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guille
authors.forename: Rémi
authors.initials: R
authors.lastname: Gillet
authors.forename: José
authors.initials: J
authors.lastname: Adélaide
authors.forename: Véronique
authors.initials: V
authors.lastname: Gelsi-Boyer
authors.forename: Christine
authors.initials: C
authors.lastname: Arnoulet
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
authors.forename: Marie-Joelle
authors.initials: MJ
authors.lastname: Mozziconacci
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Anne
authors.initials: A
authors.lastname: Murati
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002872:Chromosome Deletion; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D017422:Sequence Analysis, DNA