title: BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.
abstract: Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.
authors.affiliation: Institut Gustave Roussy, Villejuif, France;
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Virginie
authors.initials: V
authors.lastname: Chesnais
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Laurianne
authors.initials: L
authors.lastname: Scourzic
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Raphael
authors.initials: R
authors.lastname: Itzykson
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Véronique
authors.initials: V
authors.lastname: Gelsi-Boyer
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Hiraku
authors.initials: H
authors.lastname: Mori
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Agnes
authors.initials: A
authors.lastname: Guerci-Bresler
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cheze
authors.forename: Thomas
authors.initials: T
authors.lastname: Prébet
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Marion
authors.initials: M
authors.lastname: Legentil
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C411984:BCOR protein, human; C521111:BCORL1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A