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

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

  • Sci Rep. 2022 Jul 20;12(1):12420. doi: 10.1038/s41598-022-16455-1.
Angela Martinez-Monleon 1,  Hanna Kryh Öberg 1,  Jennie Gaarder 1,  Ana P Berbegall 2,  Niloufar Javanmardi 1,  Anna Djos 1,  Marek Ussowicz 3,  Sabine Taschner-Mandl 4,  Inge M Ambros 4,  Ingrid Øra 5,  Bengt Sandstedt 6,  Klaus Beiske 7,  Ruth Ladenstein 4,  Rosa Noguera 2,  Peter F Ambros 4,  Lena Gordon Murkes 8,  Gustaf Ljungman 9,  Per Kogner 10,  Susanne Fransson 11,  Tommy Martinsson 1
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, University of Gothenburg, Box 445, 405 30, Gothenburg, Sweden.
  • 2 Department of Pathology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
  • 3 Department of Pediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, 50-556, Wrocław, Poland.
  • 4 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 5 Department of Pediatric Oncology and Hematology, Clinical Sciences, Lund University, Lund, Sweden.
  • 6 Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
  • 7 Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • 8 Department of Pediatric Radiology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
  • 9 Department of Women's and Children's Health, Children's University Hospital, University of Uppsala, Uppsala, Sweden.
  • 10 Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  • 11 Department of Laboratory Medicine, University of Gothenburg, Box 445, 405 30, Gothenburg, Sweden. susanne.fransson@clingen.gu.se.
PMID: 35859155 DOI: 10.1038/s41598-022-16455-1
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 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.

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