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CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma

Karim H Saba1, Valeria Difilippo1, Emelie Styring2

  • 1Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.

NPJ Genomic Medicine
|September 25, 2024
PubMed

Insights

High-grade osteosarcoma genomic analysis reveals four subgroups with MDM2/CDK4 amplification. TP53 alterations drive CDK4 co-amplification, distinct from MDM2 chromothripsis, and promoter swapping causes ectopic gene expression.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • MDM2 and CDK4 gene amplification on chromosome 12 is a hallmark of low-grade osteosarcomas.
  • Understanding the genomic landscape of osteosarcomas with these amplifications is crucial for therapeutic strategies.

Purpose of the Study:

  • To investigate the genomic and transcriptomic profiles of osteosarcomas with MDM2 and/or CDK4 amplification.
  • To delineate distinct subgroups based on genomic alterations and their relationship with gene expression.

Main Methods:

  • High-resolution genomic and transcriptomic analyses were performed on 33 osteosarcoma samples.
  • Comparative analysis of genomic subgroups, including assessment of chromothripsis and structural alterations.
  • Identification of promoter swapping events and their impact on gene expression.

Main Results:

  • Four distinct genomic subgroups were identified, varying from near-intact to heavily rearranged genomes.
  • MDM2 amplicons showed evidence of chromothripsis, whereas TP53-rearranged cases involved initial TP53 disruption leading to CDK4 co-amplification.
  • Recurring promoter swapping events were observed, resulting in ectopic expression of genes like ELF1 due to regulatory region alterations.

Conclusions:

  • Osteosarcomas with MDM2/CDK4 amplification exhibit significant genomic heterogeneity.
  • Distinct mechanisms underlie MDM2 amplification (chromothripsis) and TP53-driven CDK4 co-amplification.
  • Promoter swapping represents a mechanism for aberrant gene expression in osteosarcoma, potentially influencing tumor behavior.

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