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Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92

Moreno, TMC; Gustafsson, G; Garwicz, Stanislaw LU ; Grander, D; Jonmundsson, GK; Frost, BM; Makipernaa, A; Rasool, O; Savolainen, ER and Schmiegelow, K, et al. (2002) In Leukemia 16(10). p.2037-2045
Abstract
Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the... (More)
Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P < 0.001), T cell phenotype (P < 0.001) and mediastinal mass (P < 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P < 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P < 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment. (Less)
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published
subject
keywords
children, acute lymphoblastic leukaemia (ALL), prognosis, ARF, INK4 deletio, p16
in
Leukemia
volume
16
issue
10
pages
2037 - 2045
publisher
Nature Publishing Group
external identifiers
  • wos:000178589600016
  • pmid:12357355
  • scopus:0036799357
ISSN
1476-5551
DOI
10.1038/sj.leu.2402697
language
English
LU publication?
yes
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ac36aa61-257c-45e9-a7c9-361a77ac1bac (old id 325535)
date added to LUP
2007-11-02 12:19:41
date last changed
2017-02-26 04:18:11
@article{ac36aa61-257c-45e9-a7c9-361a77ac1bac,
  abstract     = {Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P &lt; 0.001), T cell phenotype (P &lt; 0.001) and mediastinal mass (P &lt; 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P &lt; 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P &lt; 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment.},
  author       = {Moreno, TMC and Gustafsson, G and Garwicz, Stanislaw and Grander, D and Jonmundsson, GK and Frost, BM and Makipernaa, A and Rasool, O and Savolainen, ER and Schmiegelow, K and Soderhall, S and Vettenranta, K and Wesenberg, F and Einhorn, S and Heyman, M},
  issn         = {1476-5551},
  keyword      = {children,acute lymphoblastic leukaemia (ALL),prognosis,ARF,INK4 deletio,p16},
  language     = {eng},
  number       = {10},
  pages        = {2037--2045},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92},
  url          = {http://dx.doi.org/10.1038/sj.leu.2402697},
  volume       = {16},
  year         = {2002},
}