Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Amplification of CDK4 and MDM2 : a detailed study of a high-risk neuroblastoma subgroup

Martinez-Monleon, Angela ; Kryh Öberg, Hanna ; Gaarder, Jennie ; Berbegall, Ana P ; Javanmardi, Niloufar ; Djos, Anna ; Ussowicz, Marek ; Taschner-Mandl, Sabine ; Ambros, Inge M and Øra, Ingrid LU orcid , et al. (2022) In Scientific Reports 12. p.1-17
Abstract

In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in... (More)

In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms' tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cyclin-Dependent Kinase 4/genetics, Gene Amplification, Humans, Neuroblastoma/pathology, Prognosis, Proto-Oncogene Proteins c-mdm2/genetics, Tumor Suppressor Protein p53/genetics
in
Scientific Reports
volume
12
article number
12420
pages
1 - 17
publisher
Nature Publishing Group
external identifiers
  • scopus:85134404786
  • pmid:35859155
ISSN
2045-2322
DOI
10.1038/s41598-022-16455-1
language
English
LU publication?
yes
additional info
© 2022. The Author(s).
id
15a06581-7be4-481c-aa9d-727848aeb5be
date added to LUP
2022-09-27 21:41:49
date last changed
2025-04-19 01:35:33
@article{15a06581-7be4-481c-aa9d-727848aeb5be,
  abstract     = {{<p>In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms' tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.</p>}},
  author       = {{Martinez-Monleon, Angela and Kryh Öberg, Hanna and Gaarder, Jennie and Berbegall, Ana P and Javanmardi, Niloufar and Djos, Anna and Ussowicz, Marek and Taschner-Mandl, Sabine and Ambros, Inge M and Øra, Ingrid and Sandstedt, Bengt and Beiske, Klaus and Ladenstein, Ruth and Noguera, Rosa and Ambros, Peter F and Gordon Murkes, Lena and Ljungman, Gustaf and Kogner, Per and Fransson, Susanne and Martinsson, Tommy}},
  issn         = {{2045-2322}},
  keywords     = {{Cyclin-Dependent Kinase 4/genetics; Gene Amplification; Humans; Neuroblastoma/pathology; Prognosis; Proto-Oncogene Proteins c-mdm2/genetics; Tumor Suppressor Protein p53/genetics}},
  language     = {{eng}},
  pages        = {{1--17}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Amplification of CDK4 and MDM2 : a detailed study of a high-risk neuroblastoma subgroup}},
  url          = {{http://dx.doi.org/10.1038/s41598-022-16455-1}},
  doi          = {{10.1038/s41598-022-16455-1}},
  volume       = {{12}},
  year         = {{2022}},
}