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Integrative genome and transcriptome analyses reveal two distinct types of ring chromosome in soft tissue sarcomas.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2014 Feb 15; Vol. 23 (4), pp. 878-88. Date of Electronic Publication: 2013 Sep 26. - Publication Year :
- 2014
-
Abstract
- Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization (FISH), global genomic copy number and gene expression data on ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1 -both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than 100 different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets.
- Subjects :
- Adult
Aged
Aged, 80 and over
Cyclin-Dependent Kinase 4 genetics
Female
Gene Amplification
Gene Expression Profiling
Genetic Association Studies
Genome, Human
HMGA2 Protein genetics
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-mdm2 genetics
Proto-Oncogene Proteins c-mdm2 metabolism
Retinoblastoma Protein genetics
Sarcoma metabolism
Sarcoma mortality
Soft Tissue Neoplasms metabolism
Soft Tissue Neoplasms mortality
Ring Chromosomes
Sarcoma genetics
Soft Tissue Neoplasms genetics
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 23
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24070870
- Full Text :
- https://doi.org/10.1093/hmg/ddt479