The osteosarcoma project aims to elucidate the epigenetic and genetic signature of osteosarcoma – a childhood cancer of the bone.

Osteosarcoma, a cancer of the bone, occurs primarily in children and young adults and accounts for approximately 5% of childhood cancers overall. The first indication of osteosarcoma is pain, which is often misjudged for more common disorders such as ‘growing pains’. As a result the diagnosis is often made at a late stage, when 15-25% of the patients have detectable metastasis. The long term survival rate for these patients is only 10-40% and has not improved in the past two decades.

Osteosarcoma is characterised by a complex array of cytogenetic abnormalities with the consequence that only very few markers exist to determine the prognosis and predict the optimal treatment of the patient. Therefore, it is highly important to obtain a comprehensive understanding of the biology behind osteosarcoma progression and metastasising, to improve the treatment and survival of these very young patients.

Research focus

Our research is founded in cancer genetic and epigenetic studies. Epigenetics describe changes in gene expression not caused by direct changes in the DNA sequence. The term epigenetics comprise: DNA methylation, histone modifications and microRNA expression. Epigenetic changes are early events in tumour development, and these alterations accumulate throughout tumour progression and metastasis formation. The identification of tumour specific epigenetic changes will therefore draw a picture of the biological events leading to osteosarcoma and metastasis formation. When these data are correlated against clinical information as survival, tumour biology and treatment response, the epigenetic changes form a solid basis for the generation of novel biomarkers for early diagnosis, prognostication, and selection of therapy.

We apply genome-wide analysis of copy number variations combined with single gene analysis. Whole epigenomic analysis is combined with gene expression studies to correlate the specific epigenetic event with both protein coding and non-coding (as microRNAs) gene expression status. The genome-wide approach is used to elucidate the general alterations of the cancer, thereby obtaining a more complete picture of the changes leading to the malignancy. The single gene analyses are used to validate the genome-wide results and for developing new biomarker assays.

Epigenetic and genetic alterations in osteosarcoma

The patient material consists of biopsies of the bone tumour, which are compared to normal bone tissue. Survival data and clinical information are the foundation for correlation studies to all the genetic and epigenetic data we obtain.

To characterise the epigenetic changes of osteosarcoma, we have identified the genome-wide DNA methylation and microRNA expression changes. To further support the biological function of these alterations, the results are compared to gene expression and copy-number changes. A number of genes and microRNAs with a potential biological implication in osteosarcoma development are now identified.

In addition, we have identified a panel of specific genomic regions undergoing significant DNA methylation changes, which holds the potential as biomarkers to determine the chemotherapeutic response in osteosarcoma patients.

Assessment of biomarkers

Our studies on osteosarcoma have created a promising foundation for the use of prognostic and predictive epigenetic biomarkers to increase the survival possibility for these young patients.

We analyse a blood sample to assess the biomarkers in a mildly invasive way, for which we have developed and patented a highly sensitive method to assess DNA methylation (MS-HRM), and have proved that we can detect a few copies of methylated DNA in a blood sample, as well as in urine from bladder and prostate cancer patients.

Future perspectives of osteosarcoma

Our future focus is to implement functional studies to determine the biological effect of the identified epigenetic changes.

As bone metastasis are often connected with other primary cancers, we will expand the studies of epigenetic alterations identified in osteosarcomas to other relevant cancer forms in order to further explore the biological mechanisms behind formation of malignant bone cells.

Epigenetic alterations are reversible and the use of FDA approved epigenetic drugs in cancer treatment has shown very promising results and the field is rapidly evolving.

Gitte Brinch Andersen
PhD student
gitteba@biomed.au.dk

Lise Lotte Hansen
Associate Professor
Lotte@biomed.au.dk

Department of Biomedicine
Aarhus University
Denmark
+45 2899 2180
http://biomed.au.dk/en/research/researchers-and-research-laboratories/g-h/hansen-lise-lotte/
http://pure.au.dk/portal/en/LOTTE@HUM-GEN.AU.DK

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