Can chordoma and osteosarcoma DNA methylation markers in the blood provide a non-invasive way to determine incomplete tumour excision, early detection of relapse, response to treatment, and the response to new targeted therapies in future trials? This project aims to answer this question.

Despite robust classification of the different subtypes of sarcomas the clinical outcome for bone cancer patients has not improved in over 30 years. There is an urgent need to establish more accurate prognoses for patients, and to predict the response to chemotherapy and radiotherapy. It has been proven that tumours shed DNA into the bloodstream, and that this tumour-derived DNA can be measured using sensitive techniques from a simple blood sample. Bone cancer patients would benefit from a non-invasive blood test, which could be used to assess treatment response to chemotherapy and radiotherapy, and to targeted therapies in clinical trials, incomplete excision, and disease relapse.

Bone cancer is essentially a disease of the genome, and cancer genomes typically contain multiple genetic changes (changes such as mutations altering the DNA sequence) and epigenetic changes (changes altering the activity of the DNA without changing its sequence). An example of the latter is the addition / removal of a chemical group (e.g. a methyl group) to / from the DNA sequence. This is called DNA methylation and these changes can have the same effect as mutations.

To identify markers that discriminate sarcoma-derived DNA from “normal DNA” the team has already investigated bioinformatically the DNA methylation profiles from approximately 800 sarcoma cases covering the majority of sarcoma subtypes, in addition to publicly online available data sets, generated from a wide variety of both normal tissues blood samples, and cancers.

The aim of this study was to identify markers that discriminate osteosarcoma and chordoma-derived tumour DNA from “normal DNA” and subsequently test the specificity and sensitivity of these tumour DNA methylation markers to validate that these markers indeed can be used to detect tumour DNA in blood samples from bone cancer patients.

The results have confirmed the specificity and sensitivity of these tumour DNA methylation markers and showed that these indeed can be used to detect tumour DNA in blood samples from osteosarcoma patients. This pilot-study represents the first step towards applying circulating tumour DNA analysis to monitor disease status, response to treatment, and to detect residual disease. Ultimately, this will provide a more personalised treatment for patients, as well as more accurate prognoses. An added benefit of such tests would subsequently result in a reduction in the schedule of often inconvenient and expensive medical imaging that patients undergo for surveillance.

The Bone Cancer Research Trust would like to thank the Clive and Sylvia Richards Charity for helping to make this project a reality.

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