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Updated: Apr 20, 2026
Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
Ring chromosomes, breakpoint clusters, and neocentromeres in sarcomas
Gemma Macchia1, Karolin H Nord, Monica Zoli
1Department of Biology, University of Bari, Bari, Italy; Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.
Abstract:
Gene amplification is relatively common in tumors. In certain subtypes of sarcoma, it often occurs in the form of ring and/or giant rod-shaped marker (RGM) chromosomes whose mitotic stability is frequently rescued by ectopic novel centromeres (neocentromeres). Little is known about the origin and structure of these RGM chromosomes, including how they arise, their internal organization, and which sequences underlie the neocentromeres. To address these questions, 42 sarcomas with RGM chromosomes were investigated to detect regions prone to double strand breaks and possible functional or structural constraints driving the amplification process. We found nine breakpoint cluster regions potentially involved in the genesis of RGM chromosomes, which turned out to be significantly enriched in poly-pyrimidine traits. Some of the clusters were located close to genes already known to be relevant for sarcomas, thus indicating a potential functional constraint, while others mapped to transcriptionally inactive chromatin domains enriched in heterochromatic sites. Of note, five neocentromeres were identified after analyzing 13 of the cases by fluorescent in situ hybridization. ChIP-on-chip analysis with antibodies against the centromeric protein CENP-A showed that they were a patchwork of small genomic segments derived from different chromosomes, likely joint to form a contiguous sequence during the amplification process.
Insights
Ring and giant marker chromosomes in sarcoma often gain stability from neocentromeres. This study identified breakpoint clusters and neocentromere origins, revealing insights into gene amplification in tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gene amplification is a common event in tumor development.
- Ring and/or giant marker (RGM) chromosomes are frequently observed in specific sarcoma subtypes.
- The origin, structure, and neocentromere formation of RGM chromosomes remain poorly understood.
Purpose of the Study:
- To investigate the origin and structure of RGM chromosomes in sarcomas.
- To identify breakpoint cluster regions involved in RGM chromosome formation.
- To characterize the genomic sequences underlying neocentromeres in RGM chromosomes.
Main Methods:
- Analysis of 42 sarcomas containing RGM chromosomes.
- Detection of double-strand break-prone regions and amplification drivers.
- Fluorescent in situ hybridization (FISH) and ChIP-on-chip analysis for neocentromere identification and characterization.
Main Results:
- Nine breakpoint cluster regions were identified in RGM chromosome genesis, enriched in poly-pyrimidine traits.
- Some clusters were near sarcoma-relevant genes, suggesting functional constraints; others mapped to heterochromatic domains.
- Five neocentromeres were detected, composed of fragmented genomic segments from various chromosomes, assembled into a contiguous sequence.
Conclusions:
- RGM chromosome formation in sarcomas involves specific breakpoint clusters with distinct genomic features.
- Neocentromeres in RGM chromosomes are assembled from diverse chromosomal origins, contributing to mitotic stability.
- This research provides novel insights into the complex mechanisms of gene amplification and chromosomal instability in sarcomas.
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