A breakthrough study partly funded by the Bone Cancer Research Trust has found that non-invasive biomarkers could potentially help to identify patients most at risk from the debilitating effects of osteosarcoma.

Although responsiveness to chemotherapy can indicate a higher chance of survival, it is not possible to predict which patients are likely to respond to treatment. Once fully-validated specific biomarkers, such as DNA methylation signatures, could allow for closer examination of patients through non-invasive methods – potentially aiding the identification of remaining tumours post-surgery, early detection of relapse, reaction to chemotherapy and responsiveness to new targeted therapies in clinical trials.

The ground-breaking research was carried out by Dr Iben Lyskjær and a team of scientists led by Professor Adrienne Flanagan at University College London. The researchers used DNA methylation signatures from 11,516 patients of which included blood samples, body tissue, non-osteosarcoma cancer samples and osteosarcoma tumour samples. Patient samples were collected at the Royal National Orthopaedic Hospital (RNOH) which is also funded by one of Bone Cancer Research Trust’s Infrastructure Grants.

DNA methylation signatures were investigated as the potential non-invasive biomarker, and 4 DNA methylation-unique osteosarcoma markers were identified. The research team then set out to measure these four methylation markers of ctDNA in matched tumours, along with blood samples from 72 osteosarcoma patients.

Commenting on the new findings Dr Iben Lyskjær, Postdoctoral Researcher at University College London, and now Assistant Professor at Aarhus University, Denmark said:

I would like to express my gratitude to the supporters at the Bone Cancer Research Trust for all their hard work. You and your commitment made this project possible, and together we can make a difference in the management of osteosarcoma.

Aims of the project

  • Identify markers that discriminate osteosarcoma tumour-derived DNA from ‘normal’ DNA
  • Test the specificity and sensitivity of these markers to validate that they can be used to detect tumour DNA in blood samples from primary bone cancer patients
  • Determine if the presence of these markers can be correlated to clinical outcomes

Key findings

ctDNA assays were positive in 63% of patients with metastatic disease at diagnosis, compared with 32% of patients with localised disease; demonstrating that circulating tumour DNA detection correlates with disease progression.

Furthermore, ctDNA was detected preoperatively in 17 patients with localised disease at diagnosis and 10 subsequently developed a disease-related event, indicating that liquid biopsy has the potential to highlight patients who are at high risk of adverse outcomes.

High levels of DNA in circulation (circulating free DNA-cfDNA) have been linked to inferior outcomes in patients with other cancers. The researchers also observed that detection of ctDNA, or high levels of cfDNA pre-operative, seem to correlate with poorer survival rates.

What are DNA methylation signatures?

Tumour cells contain multiple genetic changes (such as mutations altering the DNA sequence) and epigenetic changes (modifying the activity of the DNA without changing its sequence). An example of an epigenetic change is the addition of a chemical group, such as a methyl group, to and/or from the DNA sequence.

DNA methylation changes can cause the same effects as mutations, and tumours shed DNA carrying these genetic and epigenetic changes into the bloodstream. Using sensitive techniques from a simple blood sample, it is believed that the tumours can be identified and measured in hope of increasing early detection and survival rates.

The study has been published in the European Journal of Cancer and is freely available here.

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