title: CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients.
abstract: OBJECTIVE
  The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors.
  
  
  METHODS
  To explore, at high resolution, the frequency and size of alterations affecting this locus in adult BCR-ABL1-positive acute lymphoblastic leukemia (ALL) and to investigate their prognostic value, 112 patients (101 de novo and 11 relapsed cases) were analyzed by genome-wide single-nucleotide polymorphism arrays and gene candidate deep exon sequencing. Paired diagnosis-relapse samples were further available and analyzed for 19 (19%) cases.
  
  
  RESULTS
  CDKN2A/ARF and CDKN2B genomic alterations were identified in 29% and 25% of newly diagnosed patients, respectively. Deletions were monoallelic in 72% of cases, and in 43% of them, the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus. An analysis conducted at relapse showed an increase in the detection rate of CDKN2A/ARF loss (47%) compared with the time of diagnosis (P = 0.06). Point mutations within the 9p21 locus were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A. Of note, deletions of CDKN2A/B were significantly associated with poor outcomes in terms of overall survival (P = 0.0206), disease free-survival (P = 0.0010), and cumulative incidence of relapse (P = 0.0014).
  
  
  CONCLUSIONS
  Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR-ABL1-positive ALL. Deletions are frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes.
authors: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli" S.Orsola Malpighi Hospital, University of Bologna, Italy.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Anna
authors: A
authors: Ferrari
authors: Annalisa
authors: A
authors: Lonetti
authors: Cristina
authors: C
authors: Papayannidis
authors: Francesca
authors: F
authors: Paoloni
authors: Stefania
authors: S
authors: Trino
authors: Clelia Tiziana
authors: CT
authors: Storlazzi
authors: Emanuela
authors: E
authors: Ottaviani
authors: Federica
authors: F
authors: Cattina
authors: Luciana
authors: L
authors: Impera
authors: Maria Chiara
authors: MC
authors: Abbenante
authors: Marco
authors: M
authors: Vignetti
authors: Antonella
authors: A
authors: Vitale
authors: Leonardo
authors: L
authors: Potenza
authors: Stefania
authors: S
authors: Paolini
authors: Simona
authors: S
authors: Soverini
authors: Fabrizio
authors: F
authors: Pane
authors: Mario
authors: M
authors: Luppi
authors: Robin
authors: R
authors: Foà
authors: Michele
authors: M
authors: Baccarani
authors: Giovanni
authors: G
authors: Martinelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl