1. CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients
- Author
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Annalisa Lonetti, Francesca Paoloni, Antonella Vitale, Maria Chiara Abbenante, Leonardo Potenza, Fabrizio Pane, Robin Foà, Clelia Tiziana Storlazzi, Ilaria Iacobucci, Emanuela Ottaviani, Anna Maria Ferrari, Marco Vignetti, Michele Baccarani, Luciana Impera, Giovanni Martinelli, Stefania Paolini, Stefania Trino, Simona Soverini, Federica Cattina, Cristina Papayannidis, Mario Luppi, Iacobucci, I, Ferrari, A, Lonetti, A, Papayannidis, C, Paoloni, F, Trino, S, Storlazzi, Ct, Ottaviani, E, Cattina, F, Impera, L, Abbenante, Mc, Vignetti, M, Vitale, A, Potenza, L, Paolini, S, Soverini, S, Pane, Fabrizio, Luppi, M, Fo?, R, Baccarani, M, Martinelli, G., Iacobucci I, Ferrari A, Lonetti A, Papayannidis C, Paoloni F, Trino S, Storlazzi CT, Ottaviani E, Cattina F, Impera L, Abbenante MC, Vignetti M, Vitale A, Potenza L, Paolini S, Soverini S, Pane F, Luppi M, Foà R, Baccarani M, and Martinelli G.
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Fusion Proteins, bcr-abl ,Locus (genetics) ,Genome-wide association study ,acute lymphoblastic leukemia ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Exon ,CDKN2A ,hemic and lymphatic diseases ,CDKN2B ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Exome sequencing ,Cyclin-Dependent Kinase Inhibitor p16 ,CDKN2A/B alterations ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Oligonucleotide Array Sequence Analysis ,Sequence Deletion ,Aged, 80 and over ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Protein-Tyrosine Kinases ,medicine.disease ,Prognosis ,BCR-ABL1 ,ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ,Leukemia ,Female ,Genome-Wide Association Study - Abstract
Purpose: 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. Patients and 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. Clin Cancer Res; 17(23); 7413–23. ©2011 AACR.
- Published
- 2011