Chromosomal alterations and liquid biopsies as monitoring and prognostic biomarkers in metastatic colorectal cancer

• Applicant: Dr. Nerma Crnovrsanin
• Subject Area: General and Visceral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513004649

Colorectal cancer represents one of the most prevalent cancers worldwide and is the second leading cause of cancer related mortality, especially in patients with metastasis. The therapy is multimodal and is majorly depending on the TNM-staging. While localized tumors can be cured by radical surgery and with or without systemic chemotherapy, the treatment strategies in metastasized tumors are more complex and inconsistent. Patients whose metastases are initially unresectable receive systemic treatment. Depending on the response to the chemotherapy the patient can become eligible for a further therapy in curative intent. There are no clear recommendations for a diagnostic tool to monitor therapy response. Currently it is performed by a combination of computed tomography (CT) imaging and determination of CEA (Carcinoembryonic antigen). Both principles have their limits, and a more accurate monitoring of disease status is needed. DNA alterations such as gene point mutations, somatic copy number aberrations (SCNA) and structural variants (SVs) are the key factors in colorectal carcinogenesis and are one of the main emphases in the research of the host institution. With the development of genomic technologies, biomarker development is increasingly coming to the fore as well. Liquid biopsy analysis of circulating cell-free DNA (cfDNA) from peripheral blood is becoming a valuable diagnostic tool in oncology. This project will focus on patients with metastatic colorectal cancer and address the unmet clinical needs ‘how to treat’ and ‘when to treat’ those patients with systematic therapy. The first part of the project will investigate genes affected by structural variants (copy-number variation associated chromosomal breaks) in metastatic colorectal cancer and their role in the response to chemotherapy. Tissue from patients who participated in two prospective multicenter trials will be analyzed by deep whole genome sequencing (WGS) and used to detect the genomic positions of SCNA - associated chromosomal breakpoints and the involved genes. The aim is to identify structural variants who are responsible for a better or worse response to a systemic chemotherapy. The second part of the project will focus on the application of cell-free circulating tumor DNA (ctDNA) technologies for treatment response monitoring in comparison to the established standard of care like CT-imaging and CEA (Carcinoembryonic antigen). Liquid biopsies are and will be collected from more than two prospective multicenter trials before and after the systemic therapy and during the follow ups and analyzed with different ctDNA technologies. The overarching aim is to determine the optimal strategy to complement and/or partly replace the current standard of care tools for treatment response monitoring of patients with metastasized colorectal cancer.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Hosts: Dr. Remond Fijneman; Professor Dr. Gerrit Meijer