Abstract
BackgroundPatients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NETs) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.Materials and MethodsSuspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.ResultsA set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.ConclusionsWe propose new potential protein biomarker candidates for classifying WD-SI-NETs at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NETs and their eventual use in diagnostics.
Highlights
Neuroendocrine tumors (NETs) are rare, life-threatening, malignant solid tumors, which arise in hormone-secreting tissue of the diffuse neuroendocrine system
The protein profiles of nine targets, namely insulin-like growth factor-binding protein 2 (IGFBP2), insulin-like growth factor 1 (IGF1), SH3KBP1-binding protein 1 (SHKBP1), ETS1, interleukin 1 alpha (IL1a), STX2, mastermind-like protein 3 (MAML3), early growth response protein 3 (EGR3) and X-linked inhibitor of apoptosis (XIAP) were verified as significant contributors to tumor classification
Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NETs and their eventual use in diagnostics
Summary
Neuroendocrine tumors (NETs) are rare, life-threatening, malignant solid tumors, which arise in hormone-secreting tissue of the diffuse neuroendocrine system. During the early stages of disease, NETs are generally slow-growing and asymptomatic, whereas at a later stage, tumor metastasis to the liver appears along with hormonal hypersecretion This generally leads to well defined and debilitating clinical syndromes such as the flushing and diarrhea of the carcinoid syndrome. Well-differentiated small intestinal neuroendocrine tumor (WD-SI-NET) patients are predominantly diagnosed with a delay of three to four years at a metastatic stage of the disease, hindering possible curative treatment. Several variables, such as the rarity and heterogeneity of these malignancies, the multiplicity of NET classification systems and the historical lack of well-designed clinical trials may contribute to the diagnostic delay. New approaches for earlier detection and improved monitoring of the disease are required
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