Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH

ABSTRACT: Background: Osteosarcoma (OS) tumors and derived cell lines are characterized by complex chromosomal abnormalities. The availability of molecular genome profiling techniques such as array CGH have markedly enabled the high-resolution genome analysis of tumor genomes, as well as helped elucidate the mechanisms leading to their complexity. The identification of tumor-specific genomic profiles is currently the focus of many array CGH studies, but there have been no analyses to date documenting the genomic signatures consistent with chromosomal instability mechanisms in OS. Results: In this study we utilized high-resolution oligonucleotide array CGH to interrogate recurrent signatures of genomic imbalance in 10 OS tumors that were consistent with the breakage fusion bridge(BFB) mechanism. Comparative analysis of the tumors showed that they exhibited varying levels of genomic imbalance. The analysis also highlighted three chromosomal regions (6p21 ~ p22, 8q24 and 17p11.2 ~ p12) that were consistently involved in high level gain or amplification events. These three regions have been previously shown by us to be not only involved in high-level imbalance in OS-derived cell lines, but also to exhibit similar imbalance profiles consistent with BFB-related events. Karyotype and dual-color FISH analysis showed that repeated rearrangements of these unstable chromosomes through BFB cycles may create a heterogeneous pattern of copy number alterations. Conclusions: This genome-wide analysis is the first to utilize oligonucleotide array CGH and FISH analysis to derive possible genomic signatures of chromosomal instability in OS tumors. Perpetuation of the BFB cycle will create a heterogeneous pattern of copy number alterations by repeated rearrangement of the unstable tumor genome., thereby generating diverse phenotypes The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms events leading to tumor development could result in the identification of prognostic markers and therapeutic targets. Keywords: osteosarcoma, chromosomal instability, gene amplification, breakage-fusion-bridge cycle, oligonucleotide array comparative genomic hybridization

ORGANISM(S): Homo sapiens

PROVIDER: GSE9654 | GEO | 2007/11/21

SECONDARY ACCESSION(S): PRJNA103525

REPOSITORIES: GEO