Role of Amplification of Chromosome 6P12-P21 in Human Osteosarcoma
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Osteosarcoma is an aggressive bone malignancy with neither reliable prognostic or predictive biomarkers nor drugs for targeted therapy. It is the most common malignant tumour of bone, predominantly occurring in adolescents. Currently, the mainstay of treatment is surgical resection in combination with multi-agent chemotherapy. Understanding of the genetic basis of osteosarcoma has been impeded by the complex and heterogeneous nature of genome-wide rearrangements in tumour cells. It has been shown that the genetic complexity arises as a result of unusually high levels of chromosomal instability (CIN), which causes numerous copy number changes. This extensive CIN leads to genomic gains or amplifications of various chromosomal regions including, frequently, a portion of chromosome 6 between cytobands 6p12-p21. The high frequency of these particular rearrangements implies they could confer selective advantage to tumour cells during osteosarcoma development. In the present study, we examined the relationship between genomic gain of chromosome 6p12-p21, including increased copy number of the osteogenic transcription factor gene RUNX2, and measures of CIN as well as tumour response to chemotherapy in a retrospective cohort of osteosarcoma patients. The present study demonstrates: 1) Gain and amplification events involving chromosome 6p12-p21 have been frequently reported in a variety of cancer types in addition to osteosarcoma. 2) Clusters of segmental duplications greater than 10,000 base pairs in length flank the commonly amplified region of 6p12-p21, and cytobands 6p12 and 6p21.3 are enriched in highly similar segmental duplications. 3) Interphase fluorescence in situ hybridisation (FISH) confirmed array comparative genomic hybridisation-detected copy number changes in E2F3, PIM1, and RUNX2 and identified trends between increased RUNX2 copy number and poor tumour response to chemotherapy, and between increased E2F3 copy number and CIN. 4) Interphase FISH for chromosome-specific enumeration identified a high rate of aneuploidy in the sample set. 5) Moderate to strong RUNX2 immunoreactivity, as assessed by immunohistochemistry, was present throughout the samples, and a trend was observed between high RUNX2 levels and poor tumour response to chemotherapy. Our study thus identified potential roles for genomic gain of chromosome 6p12-p21 and amplification-related overexpression of RUNX2 in the development of osteosarcoma and in resistance to chemotherapy.