Genetic and Telomere Characteristics of High of Grade Soft Tissue Sarcomas

Soft tissue sarcomas (STSs) are a rare group of cancers that can arise in any 'soft' tissue but commonly involve muscles, fat and nerves. Even following surgery and radiotherapy over 50% of tumours will recur or spread and at present, there is no reliable test that allows doctors to predict in which patients this will occur.

DNA that is not inside cells (cell-free or cfDNA) is present in very small quantities circulating in blood. In cancer patients some of this cfDNA comes from cancer cells. Analysis of cancer-derived cfDNA in patients with other cancers has shown that the quantity and characteristics of cfDNA changes with stage of disease and treatment. The researchers plan to investigate the abundance and persistence of cancer-derived cfDNA in STS patients at various stages of disease to investigate the potential role of these characteristics as biomarkers.

Selection of the genetic characters to be tracked in the patients' cfDNA is an important consideration. An established hallmark of a cancer cell is the ability to undergo an unlimited number of cell divisions. In normal human cells protective structures on the ends of chromosomes called telomeres provide a mechanism to limit the number of times a healthy cell can divide. This limitation has to be overcome in cancer cells for a tumour to form. This occurs by the activation of one of two telomere maintenance mechanisms (TMM) - either an enzyme called Telomerase or a mechanism known as Alternative Lengthening of Telomeres (ALT). In many sarcomas the activation of either TMM is associated with genetic changes (mutations) in a small number of genes. As these mutations are not present in normal cells but mark an essential feature of cancer cells (and their capacity for unlimited cell division) they are likely to be reliable markers of the presence of STS cells.

The investigators plan to develop sensitive, quantitative assays to detect TMM associated mutations in tumour derived cfDNA in the blood of patients with STSs, and track these mutations overtime. They will establish the amount of cancer-derived cfDNA in STS patients at the time of surgery, and persistence of this cfDNA during follow up visits following tumour resection and in the events of local tumour recurrence or spread (metastatic disease). Once these basic parameters are established analysis will be broadened to include other genes that are commonly mutated in STSs with a view of identifying other genetic characteristics that may also aid identification of patients at high risk of recurrence or spread. In summary all of the assays described above should facilitate better monitoring of patients with STS, and allow earlier treatment if STS recurs following surgery.