Integrative genome and transcriptome analyses reveal two distinct types of ring chromosome in soft tissue sarcomas.
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.
Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, 221 84 Lund, Sweden.
Karolin H
KH
Nord
Gemma
G
Macchia
Johnbosco
J
Tayebwa
Jenny
J
Nilsson
Fredrik
F
Vult von Steyern
Otte
O
Brosjö
Nils
N
Mandahl
Fredrik
F
Mertens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D015894:Genome, Human; D025743:HMGA2 Protein / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics; D012303:Ring Chromosomes; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D059467:Transcriptome
D025743:HMGA2 Protein; D016160:Retinoblastoma Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4