SummaryThis study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes). The near-haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near-haploidy was restricted to children of median age 7 years (range 2-15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9-54). Patients with 42-45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42-44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near-haploid and low hypodiploid groups compared to those with 42-45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.

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...

Summary Interphase fluorescence in situ hybridization (iFISH) was used independently to reveal chromosomal abnormalities of prognostic importance in a large, consecutive series of children (n = 2367) with acute lymphoblastic leukaemia (ALL). The fusions, TEL/AML1 and BCR/ABL, and rearrangements of the MLL gene occurred at frequencies of 22% (n = 447/2027) (25% in B‐lineage ALL), 2% (n = 43/2027) and 2% (n = 47/2016) respectively. There was considerable variation in iFISH signal patterns both between and within patient samples. The TEL/AML1 probe showed the highest incidence of variation (59%, n = 524/884), which included 38 (2%) patients with clustered, multiple copies of AML1. We were thus able to define amplification of AML1 as a new recurrent abnormality in ALL, associated with a poor prognosis. Amplification involving the ABL gene, a rare recurrent abnormality confined to T ALL patients, was identified for the first time. The use of centromeric probes revealed significant hidden high hyperdiploidy of 33% and 59%, respectively, in patients with normal (n = 21/64) or failed (n = 32/54) cytogenetic results. The iFISH contributed significantly to the high success rate of 91% (n = 2114/2323) and the remarkable abnormality detection rate of 89% (n = 1879/2114). This study highlights the importance of iFISH as a complementary tool to cytogenetics in routine screening for significant chromosomal abnormalities in ALL.