Identification of potential novel biomarkers in neuroendocrine tumours of the gastroenteropancreatic system.

Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are rare tumours arising in the neuroendocrine cells of the digestive system. Chromosomal instability is rarely observed in GEP-NET suggesting epigenetic changes, such as changes in microRNA (miRNA) expression, may be drivers of disease pathology. There is an unmet clinical need for novel prognostic biomarkers to enable further stratification of GEP-NET patients based on tumour behaviour and to inform treatment options. In this thesis a study of 161 GEP-NET patients demonstrates that liver metastases remain a common event despite the majority of tumours having low proliferation levels as assessed by the proliferation marker Ki-67. 28 % of the GEP-NET patients with a Ki-67 % of ≤ 2 % (G1) had stage IV disease. The results are even more striking for patients with small bowel neuroendocrine tumours (SBNET) with 54 % of G1 SBNET patients having stage IV disease. In order to identify novel prognostic biomarkers for use in patients with SBNET, 800 miRNA are quantified in 90 different tissue samples from 37 SBNET patients. This work represents the most comprehensive investigation of miRNA expression in SBNET to date. Novel miRNA are identified that have not been previously associated with SBNET tumourigenesis and disease progression. These miRNA warrant further study to better understand their contribution to disease pathology in SBNET. The most promising potential biomarkers associated with disease progression in SBNET are validated in two independent populations of SBNET patients to ensure that the results are reproducible. Further analysis demonstrates that miR-1 and miR-143-3p are the most promising candidates for use as potential novel prognostic biomarkers in SBNET patients. Further studies are warranted to determine the clinical utility of miR-1 and miR-143-3p as prognostic biomarkers and to determine if they can be used to identify patients with more aggressive disease subtypes and enable tailored treatment.Open Acces