CDKN2A/BAlterations Impair Prognosis in AdultBCR-ABL1–Positive Acute Lymphoblastic Leukemia Patients

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 ¼ 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 ¼ 0.0206), disease free-survival (P ¼ 0.0010), and cumulative incidence of relapse (P ¼ 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. Ó2011 AACR.

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

“…The prognostic significance for adult ALL is controversial. Iacobucci et al 13 reported that CDKN2A/B deletions had independent significance for lower disease-free survival in a series of 112 adult Ph-positive patients, but other authors did not show any prognostic impact. 27 No differences in outcomes were observed from a comparison of heterozygous and homozygous CDKN2A/B deletions, 12 and this suggests an important haplo-insufficiency effect 28 or concomitant inactivation of the remaining allele by epigenetic events.…”

“…[9][10][11] The prognostic implications of CNAs have been less studied in adult ALL. [12][13][14][15] IKZF1 and CDKN2A/B deletions have been associated with lower disease-free survival in adults with Philadelphia chromosome (Ph)-positive ALL, 13,14 but results from large series of Ph-negative patients are scarce. 12,15 The current study analyzed the frequency and prognostic significance of CNAs in adolescents and adults with B-cell ALL enrolled in risk-adapted protocols of the Spanish Programa Español de Tratamientos en Hematolog ıa (PETHEMA) group.…”

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

“…The OS of patients with B-ALL, particularly those with Ph -ALL carrying ≥3 gene deletions was poor with an increased CIR. Adult Ph + ALL patients carrying CDKN2A/2B deletions also exhibited a poor disease-free survival (DFS) (16). The present study evaluated the 2-year OS and RFS in different groups of patients.…”

Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics

“…Alterations in the cell-cycle pathway have been described in multiple cancers (8)(9)(10)(11)(12) and are associated with poorer clinical outcome in some tumor types (13)(14)(15), including acute lymphoblastic leukemia (9), ovarian (10), colon cancer (12), and medulloblastoma (11).…”