title: Inverse correlation between Ink4-locus deletions and ICM-DNA hyperdiploidy in childhood acute lymphoblastic leukaemia, relation to clinical characteristics and outcome.
abstract: Malignant cells from 72 children with ALL were analysed to investigate the relationship between DNA-ploidy and deletion of the Ink4 locus containing the cell-cycle regulating genes p16ink4a, p15ink4b and p14ARF. Image-DNA cytometry (ICM) was used to assess DNA index (DI), and Southern hybridisation was carried out to detect deletions of the Ink4-locus in the leukaemic cells. A DNA content equal to or exceeding 1.16, indicating hyperdiploidy, was detected in 21/72 patients (29%), 1/72 (1.3%) showed DNA-hypodiploidy, and the remaining 50 patients (69%) had a DI within normal limits. Bi-allelic deletion of at least two of the coding sequences from the Ink4 locus was observed in 23/70 (33%) patients. Mono-allelic deletions within the locus were observed in 10/70 patients (14%), and 37/70 patients (53%) had normal signals for both sequences. Out of the 70 patients that could be analysed by both techniques only two had the combination of DNA hyperdiploidy and Ink4-locus bi-allelic deletion (p = 0.004). DNA hyperdiploidy was not associated with any specific clinical characteristics, but there was a trend for a better prognosis for patients with DNA hyperdiploidy (p = 0.09). Ink4-locus deletion was associated with T-cell phenotype and higher white blood cell counts at diagnosis and poor prognosis (p = 0.0015). Multivariate analysis confirmed that Ink4-locus deletion is an independent prognostic marker and a stronger determinant of outcome than DNA ploidy. When DNA ploidy and Ink4-locus deletions were combined, novel subgroups with significantly different outcome could be observed. A group with DNA index > or = 1.16 and no Ink4-locus bi-allelic deletions had an excellent prognosis (p-EFS 0.93 at 60 months), patients with Ink4-locus bi-allelic deletion and a DNA index < 1.16 fared worst (p-EFS 0.57) and patients with no Ink4 deletions and without hyperdiploidy had an intermediate outcome (p-EFS 0.79). The reason for the inverse correlation between DNA ploidy and Ink4 deletion and their combined impact on prognosis remains unclear, and possible reasons are discussed.
authors.affiliation: Radiumhemmet Research Laboratory, Cancer Centre Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
authors.forename: T C
authors.initials: TC
authors.lastname: Moreno
authors.forename: S
authors.initials: S
authors.lastname: Widell
authors.forename: M
authors.initials: M
authors.lastname: Czader
authors.forename: D
authors.initials: D
authors.lastname: Grandér
authors.forename: S
authors.initials: S
authors.lastname: Söderhäll
authors.forename: G
authors.initials: G
authors.lastname: Gustafsson
authors.forename: S
authors.initials: S
authors.lastname: Einhorn
authors.forename: A
authors.initials: A
authors.lastname: Porwit
authors.forename: M
authors.initials: M
authors.lastname: Heyman
mesh_terms: D000206:Actuarial Analysis; D000293:Adolescent; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020732:Cytogenetic Analysis; D004171:Diploidy; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor / Q000235:genetics; D018816:Genes, cdc; D006801:Humans; D007223:Infant; D008297:Male; D005810:Multigene Family / Q000235:genetics; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins