Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.

Abstract

Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the MDM2 and CDK4 genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies targeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarcomas.

• Authors: Mossane Stocker, Louis-Romée Le Nail, Hubert De Belenet, Jay S Wunder, Irene L Andrulis, Nalan Gokgoz, Nicolas Levy, Jean-Camille Mattei, Sylviane Olschwang
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 11 Issue 6 Pg. 3271-3284 ( 2021) ISSN: 2156-6976 [Print] United States
• PMID: 34249461 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2021.