Authors
G. BOONS (1), T. VANDAMME (1), W. LYBAERT (2), G. ROEYEN (3), T. RONDOU (4), K. PAPADIMITRIOU (1), K. JANSSENS (5), W. DEMEY (6), I. DERO (7), G. VAN CAMP (1), M. PEETERS (1), K. OP DE BEECK (1) / [1] University of Antwerp/Antwerp University Hospital, Edegem, Belgium, Center for Oncological Research, [2] AZ Nikolaas, Sint-Niklaas, Belgium, Department of Oncology, [3] Antwerp University Hospital, Edegem, Belgium, Department of Hepatobiliary, Endocrine and Transplantation Surgery, [4] AZ Rivierenland BORNEM, Bornem, Belgium, Department of Oncology, [5] University of Antwerp/Antwerp University Hospital, Edegem, Belgium, Center of Medical Genetics, [6] AZ Klina, Brasschaat, Belgium, Department of Medical Oncology, [7] Sint Augustinus Ziekenhuis GZA, Antwerp, Belgium, Department of Gastroenterology
Introduction
Recent studies, including our proof-of-concept study, demonstrated the possibility to detect tumor-derived molecular alterations in cell-free DNA (cfDNA) from plasma of patients with a gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). The lack of highly sensitive and specific blood-based biomarkers for GEP-NEN patients, therefore, warrants an in-depth evaluation of the biomarker potential of cfDNA.
Aim
Our goal was to detect tumor-associated copy number alterations (CNAs) in cfDNA from GEP-NEN patients to molecularly characterize the tumor and estimate tumor fraction, and to evaluate these parameters over time.
Methods
Metastatic GEP-NEN patients were included within NETwerk, a multi-institutional network of eight hospitals in Belgium. cfDNA was extracted from plasma of all patients and subjected to shallow whole-genome sequencing (WGS). Then, detection of CNAs and estimation of tumor fraction were performed using the R-based tool ichorCNA. Clinicopathological data were collected from all patients to correlate experimental and clinical findings.
Results
In total, 80 samples of 29 metastatic GEP-NEN patients were analyzed using shallow WGS. All patients had a well-differentiated GEP-NEN and primary sites were pancreas (N=15), small intestine (N=10), colon (N=1), caecum (N=1), ileocaecal valve (N=1) and pylorus (N=1). In 32 cfDNA samples from 13 patients (45%), CNAs with a tumor fraction higher than 3% could be detected. CNAs were detected in 60% of included pancreatic NEN (PNEN) patients and CNA patterns were similar to patterns detected in PNEN tumor tissues, e.g. whole-chromosome gains of chromosomes 4, 5, 7, 9, 12, 13, 14, 17, 18, 19 and 20. Tumor fractions changed over time, which could be linked to changes in tumor burden, tumor progression or treatment response according to RECIST1.1 criteria and will be further examined, including in additional samples that are being collected.
Conclusions
Cell-free DNA of metastatic GEP-NEN patients contains CNAs that correspond to CNA patterns seen in tumor tissue samples. CNAs can be used to quantify the tumor fraction in cfDNA over time, which will be linked to tumor evolution in our ongoing study.
