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Article Dans Une Revue Blood Advances Année : 2021

Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study

1 CRCINA-ÉQUIPE 7 - Innate Immunity and Immunotherapy
2 Service d'hématologie [Angers]
3 UFR Santé [UNIV Angers]
4 MINT - Micro et Nanomédecines Translationnelles
5 (UMR_S1131 / U1131) - Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris]
6 Laboratoire de Biologie Cellulaire [AP-HP Hôpital Saint-Louis]
7 CHU-Brest-Hemato - CHRU Brest - Service d'Hématologie
8 Service d'hématologie clinique [CHRU Brest]
9 Service d'hématologie clinique [CH Lens]
10 Service des maladies du sang [Angers]
11 Service d'Hématologie [Bordeaux]
12 Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
13 Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM]
14 CRCM - Centre de Recherche en Cancérologie de Marseille
15 Institut Bergonié [Bordeaux]
16 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
17 Service d'Hématologie Cellulaire [Lille]
18 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
19 Service d'Hématologie biologique [CHU Limoges]
20 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
21 Service d'Hématologie [Nantes]
22 Service d'hématologie biologique [CHU de Dijon]
23 Service d'Hématologie Clinique [CHRU Nancy]
24 Service de Cancérologie Biologique [CHU Poitiers]
25 Service d'Hématologie [CH Annecy]
26 Service d'hématologie biologique [Centre Hospitalier Lyon Sud - HCL]
27 Centre Hospitalier Perigueux
28 Laboratoire CERBA [Saint Ouen l'Aumône]
29 Hôpital Cochin [AP-HP]
30 Laboratoire d’Hématologie [CHU Henri-Mondor - APHP]
31 UPEC Médecine - Université Paris-Est Créteil Val-de-Marne - Faculté de médecine
32 Laboratoire d'Hématologie et d'Immunologie [CHU Henri Mondor]
33 IMRB - Institut Mondor de Recherche Biomédicale
34 Service d'Hématologie [CH Perpignan]
35 Centre Hospitalier de Roubaix
36 Service d'hématologie et d'Oncologie [CHU Grenoble]
37 AU - Avignon Université
38 Service d’Onco-Hématologie et Médecine interne [Le Mans]
39 CH Rochefort - Centre Hospitalier de Rochefort
40 ECSTRRA [CRESS - U1153 / UMR_A 1125] - Epidemiology and Clinical Statistics for Tumor, Respiratory, and Resuscitation | Epidémiologie Clinique, STatistique, pour la Recherche en Santé
41 Département d'anatomopathologie [CHU Cochin]
42 Unité d'hématologie et de transplantation
43 CIC-1427 - CIC Saint Louis
Jeremie Riou
Gabriel Etienne
Olivier Kosmider
Gérard Socié

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 5 276). Four genomic groups were identified: patients with TP53 mutation; patients with $1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (highrisk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or highrisk 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.

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Cancer
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Dates et versions

inserm-03187575 , version 1 (01-04-2021)

Identifiants

Citer

Damien Luque Paz, Jeremie Riou, Emmanuelle Verger, Bruno Cassinat, Aurélie Chauveau, et al.. Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study. Blood Advances, 2021, 5, pp.1442 - 1451. ⟨10.1182/bloodadvances.2020003444⟩. ⟨inserm-03187575⟩
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