A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups

Abstract

Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region. (Blood. 2009;113:100-107) IntroductionGenetic alterations including chromosomal translocation, promoter hypermethylation, somatic mutation, and gene deletion are thought to play a key role in oncogenesis. Alterations of the 9p21 locus have been implicated in many types of cancer, indicating a role for the tumor suppressor genes CDKN2A (MTS1) and CDKN2B (MTS2), which encode for p16 INK4a /p14 ARF and p15 INK4b , respectively. 1 Loss of cell proliferation control and regulation of the cell cycle are known to be critical to cancer development. 2 Both p16 INK4a and p15 INK4b specifically inhibit cyclin/CDK-4/6 complexes that block cell division during the G 1 /S phase of the cell cycle. 3 It has been reported that CDKN2A and CDKN2B are frequently inactivated in various hematologic malignancies. 1,4 Loss of heterozygosity (LOH) of chromosome arm 9p, including the CDKN2A locus, is one of the most frequent genetic events in childhood acute lymphoblastic leukemia (ALL), suggesting inactivation of the second allele or, possibly, haploinsufficiency. [5][6][7][8] Haploinsufficiency of a tumor suppressor gene, eg, CDKN2A, has been shown to be adequate to promote tumor progression. [9][10][11] Homozygous deletion of CDKN2A has been suggested as the dominant mechanism of its inactivation in leukemogenesis. 12 However, the reported frequencies of both heterozygous and homozygous deletions in childhood ALL vary, 9% to 27% and 6% to 33% in B-cell precursor (BCP) respectively. 13 Similarly, the frequency of hypermethylation of the CDKN2A promoter has been reported to vary from 0% to 40% in childhood ALL. [14][15][16][17][18][19] Althou...

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

“…29,30 Recently, deletions of IKZF1 were shown to be a predictor of poor outcome in high-risk pediatric B-cell progenitor ALL. 31 However, high hyperdiploid ALLs are rarely grouped as high risk.…”

Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

“…These ''driving'' mutations most likely involve a myriad of different genes giving each cancer case its individual ''face'' but are ultimately converging onto the modification of a finite number of critical pathways. Secondary alterations are well known to occur in hematological malignancies (Bergsagel and Kuehl 2001;Sulong et al 2009). The novel gene fusions presented here might represent secondary lesions that occur at a later time point in prostate oncogenesis.…”

FISH Analysis of 9p21 Deletion in Egyptian Childhood Acute Lymphoblastic Leukemia Patients: Relation to Prognosis and Disease Outcome

“…This comes in line with four large studies by Woo et al [18] , Mullighan et al [21] , Perez-Vera et al [22] and Sulong et al [10] , they utilized FISH technique with a commonly used commercial probe to study 9p21 deletion in patients with ALL and the deletion frequency ranged from 20-27%. On the other hand this frequency is higher than that recorded by Kuchinskaya et al [12] who identified this deletion in (15.7%) of patients, but is lower than a study done by Schiffman et al [4] who reported this deletion in 29/45 (64.4%) patients and Karkucak et al [19] who detected 9p21 deletion in 8/22 (36%)of patients.…”

“…CDKN2A is a tumour suppressor gene that encodes two proteins, and acts through the Rb and mouse double minute 2 (MDM2) pathways. CDKN2B (p15) is a tumour suppressor gene, the action of which through the Rb pathway is complementary to CDKN2A (p16) [10,11] . MTAP is located approximately 100 kb telomeric to CDKN2A and encodes methylthioadenosine phosphorylase, an enzyme involved in purine and methionine metabolism.…”