title: Mutations and prognosis in primary myelofibrosis.
abstract: Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. amvannucchi@unifi.it
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: T L
authors.initials: TL
authors.lastname: Lasho
authors.forename: P
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: F
authors.initials: F
authors.lastname: Biamonte
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.forename: A
authors.initials: A
authors.lastname: Pereira
authors.forename: C
authors.initials: C
authors.lastname: Finke
authors.forename: J
authors.initials: J
authors.lastname: Score
authors.forename: N
authors.initials: N
authors.lastname: Gangat
authors.forename: C
authors.initials: C
authors.lastname: Mannarelli
authors.forename: R P
authors.initials: RP
authors.lastname: Ketterling
authors.forename: G
authors.initials: G
authors.lastname: Rotunno
authors.forename: R A
authors.initials: RA
authors.lastname: Knudson
authors.forename: M C
authors.initials: MC
authors.lastname: Susini
authors.forename: R R
authors.initials: RR
authors.lastname: Laborde
authors.forename: A
authors.initials: A
authors.lastname: Spolverini
authors.forename: A
authors.initials: A
authors.lastname: Pancrazzi
authors.forename: L
authors.initials: L
authors.lastname: Pieri
authors.forename: R
authors.initials: R
authors.lastname: Manfredini
authors.forename: E
authors.initials: E
authors.lastname: Tagliafico
authors.forename: R
authors.initials: R
authors.lastname: Zini
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Zoi
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.forename: A
authors.initials: A
authors.lastname: Duncombe
authors.forename: D
authors.initials: D
authors.lastname: Pietra
authors.forename: E
authors.initials: E
authors.lastname: Rumi
authors.forename: F
authors.initials: F
authors.lastname: Cervantes
authors.forename: G
authors.initials: G
authors.lastname: Barosi
authors.forename: M
authors.initials: M
authors.lastname: Cazzola
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human