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CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma.
Saba, Karim H; Difilippo, Valeria; Styring, Emelie; Nilsson, Jenny; Magnusson, Linda; van den Bos, Hilda; Wardenaar, René; Spierings, Diana C J; Foijer, Floris; Nathrath, Michaela; Haglund de Flon, Felix; Baumhoer, Daniel; Nord, Karolin H.
Affiliation
  • Saba KH; Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
  • Difilippo V; Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
  • Styring E; Department of Orthopedics, Lund University, Skåne University Hospital, Lund, Sweden.
  • Nilsson J; Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
  • Magnusson L; Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
  • van den Bos H; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
  • Wardenaar R; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
  • Spierings DCJ; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
  • Foijer F; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
  • Nathrath M; Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • Haglund de Flon F; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
  • Baumhoer D; Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
  • Nord KH; Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
NPJ Genom Med ; 9(1): 42, 2024 Sep 25.
Article in En | MEDLINE | ID: mdl-39322633
ABSTRACT
Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We discerned four major subgroups, ranging from nearly intact genomes to heavily rearranged ones, each harbouring CDK4 and MDM2 amplification or CDK4 amplification with TP53 structural alterations. While amplicons involving MDM2 exhibited signs of an initial chromothripsis event, no evidence of chromothripsis was found in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus led to co-amplification of the CDK4 locus. Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: NPJ Genom Med Year: 2024 Document type: Article Affiliation country: Sweden Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: NPJ Genom Med Year: 2024 Document type: Article Affiliation country: Sweden Country of publication: United kingdom