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

Abstract

Osteosarcoma (OS) is characterized by an unstable karyotype which typically has a heterogeneous pattern of complex chromosomal abnormalities. High-resolution array comparative genomic hybridization (CGH) in combination with interphase fluorescence in situ hybridization (FISH) analyses provides a complete description of genomic imbalances together with an evaluation of the contribution of cell-to-cell variation to copy number changes. There have been no analyses to date documenting genomic signatures consistent with chromosomal instability mechanisms in OS tumors using array CGH. In this study, we utilized high-resolution array CGH to identify and characterize recurrent signatures of genomic imbalances using ten OS tumors. Comparison between the genomic profiles identified tumor groups with low, intermediate and high levels of genomic imbalance. Bands 6p22→p21, 8q24 and 17p12→ p11.2 were consistently involved in high copy gain or amplification events. Since these three locations have been consistently associated with OS oncogenesis, FISH probes from each cytoband were used to derive an index of cellular heterogeneity for copy number within each region. OS with the highest degree of genomic imbalance also exhibited the most extreme cell-to-cell copy number variation. Significantly, the three OS with the most imbalance and genomic copy number heterogeneity also had the poorest response to preoperative chemotherapy. This genome wide analysis is the first utilizing oligonucleotide array CGH in combination with FISH analysis to derive genomic signatures of chromosomal instability in OS tumors by studying genomic imbalance and intercellular heterogeneity. This comprehensive genomic screening approach provides important insights concerning the mechanisms responsible for generating complex genomes. The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms leading to OS tumor development could result in the identification of prognostic markers and therapeutic targets.

Genomic Alterations and Allelic Imbalances Are Strong Prognostic Predictors in Osteosarcoma

“…Furthermore, patients with tumors showing above average LOH scores developed recurrent disease more often than did patients with tumors showing low LOH scores. A correlation between chromosomal imbalances and the prognosis of patients has recently been shown not only in osteosarcomas, but also in other tumors, including gastric carcinomas, but the biological basis of these observations is poorly understood (13,17,18). The high LOH scores in osteosarcomas with a poor response to chemotherapy found in our study might represent an imbalanced loss of various genes involved in cell cycle and apoptosis regulation and therefore might reflect a more aggressive phenotype with a potential survival advantage against chemotherapy.…”

Fusion between cancer cells and myofibroblasts is involved in osteosarcoma

“…Certain genetic predispositions have been observed to correlate with osteosarcoma, including hereditary retinoblastoma and Li-Fraumeni syndrome, which are characterized by a high risk of developing osteosarcoma (2,3). Genetic aberrations that accompany osteosarcoma have been identified; however, osteosarcoma is characterized by karyotypes which exhibit a high degree of complexity (4,5). Understanding these mechanisms is clearly crucial to osteosarcoma therapy.…”

Profiling of Chemonaive Osteosarcoma and Paired-Normal Cells Identifies EBF2 as a Mediator of Osteoprotegerin Inhibition to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis

“…This is supported by the fact that the comparative genomic hybridization profiling of the primary tumor samples used for the studies included herein revealed almost complete chromosomal integrity (data not shown). In stark contrast, samples isolated from advanced tumors showed a panoply of karyotypic alterations (39).…”