Background. This locus 9p21, containing the p16/CDKN2A (cyclindependent kinase inhibitor 2a) tumor suppressor gene and two other related genes, p14/ARF and p15/CDKN2B, is a major target in the pathogenesis of a number of human tumors. Patients and methods. In order to assess whether and how it is inactivated in adult BCR-ABL1-positive ALL, we studied 112 adult patients: 78 (70%) were de novo ALL, 15 (13%) were unpaired relapsed cases and 19 (17%) were paired relapsed cases. Their median age was 53 years (range: 18-76) and their median blast percentage was 90% (range, 18-99). Affymetrix single nucleotide polymorphism (SNP) arrays were used to identify at a high resolution copy number changes on 9p21. Mutation screening of all exons by cloning and subsequent sequencing were also performed. Results. SNP array analysis revealed CDKN2A/ARF and CDKN2B genomic alterations in 33% and 24% of diagnosed patients, respectively. In 70% of cases, deletions were limited to CDKN2A/CDKN2B genes, whereas in 30% they also affected neighbour genes and/or the entire chromosome 9. In order to assess whether CDKN2A loss is responsible for progression, 34 patients were analyzed at the time of relapse and a significant increase in the detection rate of CDKN2A/ARF loss (53%) compared to diagnosis (P=0.04) was found. In contrast, CDKN2B deletions were found to be not significantly different between diagnosis and relapse (41% vs. 24%, P=0.07). The mutation screening of all exons showed that the 9p21 locus is rarely affected by point mutations, since we only identified the D146N and the R128 in the exon 2 of CDKN2A/ARF and the P83 silent mutation in the exon 2 of CDKN2B gene. These mutations were mutually exclusive and were found in only single cases. Conclusions. Loss of the tumor suppressor gene CDKN2A/ARF by genomic deletions is a frequent event in adult Ph+ ALL and it is involved in disease progression. Supported by: European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, Ateneo RFO grants, PRIN 2008, Project of integratad program (PIO), Programma di Ricerca Regione, Università 200-2009.
LOSS OF THE TUMOR SUPPRESSOR GENE CDKN2A/ARF IS FREQUENTLY DELETED BUT NOT MUTATED IN BCR-ABL1-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS
Ferrari A;IACOBUCCI, ILARIA;LONETTI, ANNALISA;PAPAYANNIDIS, CRISTINA;PAOLINI, STEFANIA;Parisi S;ABBENANTE, MARIACHIARA;SOVERINI, SIMONA;MARTINELLI, GIOVANNI
2010
Abstract
Background. This locus 9p21, containing the p16/CDKN2A (cyclindependent kinase inhibitor 2a) tumor suppressor gene and two other related genes, p14/ARF and p15/CDKN2B, is a major target in the pathogenesis of a number of human tumors. Patients and methods. In order to assess whether and how it is inactivated in adult BCR-ABL1-positive ALL, we studied 112 adult patients: 78 (70%) were de novo ALL, 15 (13%) were unpaired relapsed cases and 19 (17%) were paired relapsed cases. Their median age was 53 years (range: 18-76) and their median blast percentage was 90% (range, 18-99). Affymetrix single nucleotide polymorphism (SNP) arrays were used to identify at a high resolution copy number changes on 9p21. Mutation screening of all exons by cloning and subsequent sequencing were also performed. Results. SNP array analysis revealed CDKN2A/ARF and CDKN2B genomic alterations in 33% and 24% of diagnosed patients, respectively. In 70% of cases, deletions were limited to CDKN2A/CDKN2B genes, whereas in 30% they also affected neighbour genes and/or the entire chromosome 9. In order to assess whether CDKN2A loss is responsible for progression, 34 patients were analyzed at the time of relapse and a significant increase in the detection rate of CDKN2A/ARF loss (53%) compared to diagnosis (P=0.04) was found. In contrast, CDKN2B deletions were found to be not significantly different between diagnosis and relapse (41% vs. 24%, P=0.07). The mutation screening of all exons showed that the 9p21 locus is rarely affected by point mutations, since we only identified the D146N and the R128 in the exon 2 of CDKN2A/ARF and the P83 silent mutation in the exon 2 of CDKN2B gene. These mutations were mutually exclusive and were found in only single cases. Conclusions. Loss of the tumor suppressor gene CDKN2A/ARF by genomic deletions is a frequent event in adult Ph+ ALL and it is involved in disease progression. Supported by: European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, Ateneo RFO grants, PRIN 2008, Project of integratad program (PIO), Programma di Ricerca Regione, Università 200-2009.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
