MDM2 amplification in rod-shaped chromosomes provides clues to early stages of circularized gene amplification in liposarcoma

• DOI: 10.1038/s42003-024-06307-1
• Publication Date: 2024-05-20T12:01:50Z
• Authors: Saskia Sydow; Paul Piccinelli; Shamik Mitra; Panagiotis Tsagkozis; Asle Hesla; Camila B. R. De M...; Jan Köster; Linda Magnusson; Jenny Nilsson; Adam Ameur; René Wardenaar; Floris Foijer; Diana Spierings; Fredrik Mertens
• Keywords: Pair 12/genetics; 0301 basic medicine; Chromothripsis; Chromosomes, Human, Pair 12; QH301-705.5; Gene Amplification; Genetics and Genomics; Genetik och genomik; Proto-Oncogene Proteins c-mdm2; Liposarcoma; Medicinsk genetik och genomik; Chromosomes; Article; Medical Genetics and Genomics; 03 medical and health sciences; Humans; Proto-Oncogene Proteins c-mdm2/genetics; Ring Chromosomes; Liposarcoma/genetics; Biology (General); Human

AbstractWell-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings. Both types of amplicons share the same spectrum of structural variants (SVs), show higher SV frequencies in Chr12 than in co-amplified segments, have SVs that fuse the telomeric ends of co-amplified chromosomes, and lack interspersed deletions. Combined with the finding of cells with transient rod-shaped structures in tumors with ring chromosomes, this suggests a stepwise process starting with the gain of Chr12 material that, after remodeling which does not fit with classical chromothripsis, forms a dicentric structure with other chromosomes. Depending on if and when telomeres from other chromosomes are captured, circularized or linear gain of 12q sequences will predominate.