Improving colorectal cancer detection and treatment follow-up through the development of a novel methylation assay.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide and is ranked second in terms of mortality (1). Nowadays, the gold standards for screening, diagnosis and follow-up of CRC all have important drawbacks. In light of these limitations, there is a need for new, non-invasive and accurate techniques. During the last years, liquid biopsies have been intensively studied as a potential novel method for the screening, detection and follow-up of CRC. Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or blood, are sampled and analyzed. Liquid biopsies of peripheral blood, for example, are used for the detection of circulating tumor DNA (ctDNA). This DNA originates from a tumor as a result of apoptosis and necrosis of cancer cells, thereby releasing their DNA into the bloodstream. CtDNA liquid biopsies are suitable for diagnosis as ctDNA can even be detected in the plasma of early-stage cancer patients. Analysis of ctDNA in CRC patients has already been studied. However, until now, a strong focus existed on the detection of tumor specific mutations, which has important limitations. We have strong published and preliminary data showing that specific epigenetic alterations can be used as universal biomarkers in different types of cancers. We aim to further characterize these epigenetic signatures in colorectal adenoma and carcinoma. Preliminary data of our research group has shown that methylation of GSDME, a known tumor suppressor gene, is a potential detection marker for CRC (2). Furthermore, we have demonstrated that NPY methylation in ctDNA is a good marker for total tumor burden and can be used for the follow-up of metastatic CRC patients (3). Therefore, in this project, we will develop a novel digital droplet PCR assay for liquid biopsies (plasma samples) that can detect GSDME methylation in ctDNA. We will study GSDME methylation in patients with CRC, colon adenomas and healthy subjects to determine whether this test can be used for CRC detection and screening. After we have validated this GSDME assay for CRC, we will conduct a prospective multicenter trial investigating the use of both GSDME and NPY methylation analysis in liquid biopsies to guide treatment in metastatic CRC. We will investigate whether liquid biopsies have the ability to detect progressive disease earlier than standard follow-up based on CT-imaging and whether adapting treatment based on liquid biopsies can improve progression free survival.

Keywords:CANCER THERAPY, CANCER BIOMERKERS, CANCER RESEARCH

Disciplines:Cancer biology, Cancer therapy