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Inverse correlation between Ink4‐locus deletions and ICM‐DNA hyperdiploidyin childhood acute lymphoblasticleukaemia, relation to clinicalcharacteristics and outcome

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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 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.
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Keywords: DNA index; childhood ALL; image DNA cytometry; p14ARF; p16ink4a; prognosis

Document Type: Research Article

Affiliations: 1: Radiumhemmet Research Laboratory, 2: Division of Cellular and Molecular Tumour Pathology, and 3: Division of Haematopathology, Cancer Centre Karolinska (CCK), Department of Oncology Pathology, Karolinska Hospital and Institute, Stockholm, and 4: Childhood Cancer Research Unit, Astrid Lindgrens Children's Hospital, Department of Woman and Child Health, Karolinska Hospital, Stockholm, Sweden

Publication date: December 1, 2000

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