Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma.
Osteosarcomas are copy number alteration (CNA)-rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes.
Pasic
Ivan
I
Institute of Medical Science, Department of Medical Biophysics, University of Toronto, and Program in Genetics and Genome Biology, Department of Pediatric Laboratory Medicine, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Shlien
Adam
A
Durbin
Adam D
AD
Stavropoulos
Dimitrios J
DJ
Baskin
Berivan
B
Ray
Peter N
PN
Novokmet
Ana
A
Malkin
David
D
D001859:Bone Neoplasms / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D058851:GPI-Linked Proteins; D018628:Gene Dosage / Q000235:genetics*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D022661:RNA, Untranslated; C095362:limbic system-associated membrane protein