Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.
Fiche publication
Date publication
mars 2021
Journal
Blood advances
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GIRODON François
Tous les auteurs :
Luque Paz D, Riou J, Verger E, Cassinat B, Chauveau A, Ianotto JC, Dupriez B, Boyer F, Renard M, Mansier O, Murati A, Rey J, Etienne G, Mansat-De Mas V, Tavitian S, Nibourel O, Girault S, Le Bris Y, Girodon F, Ranta D, Chomel JC, Cony-Makhoul P, Sujobert P, Robles M, Ben Abdelali R, Kosmider O, Cottin L, Roy L, Sloma I, Vacheret F, Wemeau M, Mossuz P, Slama B, Cussac V, Denis G, Walter-Petrich A, Burroni B, Jézéquel N, Giraudier S, Lippert E, Socié G, Kiladjian JJ, Ugo V
Lien Pubmed
Résumé
We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
Référence
Blood Adv. 2021 Mar 9;5(5):1442-1451