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.

CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients / 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, Leonardo; Paolini, S; Soverini, S; Pane, F; Luppi, Mario; Foà, R; Baccarani, M; Martinelli, G.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 17:(2011), pp. 7413-7423. [10.1158/1078-0432.CCR-11-1227]

CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients.

POTENZA, Leonardo;LUPPI, Mario;
2011

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.
17
7413
7423
CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients / 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, Leonardo; Paolini, S; Soverini, S; Pane, F; Luppi, Mario; Foà, R; Baccarani, M; Martinelli, G.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 17:(2011), pp. 7413-7423. [10.1158/1078-0432.CCR-11-1227]
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, Leonardo; Paolini, S; Soverini, S; Pane, F; Luppi, Mario; Foà, R; Baccarani, M; Martinelli, G.
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