Identification of candidate serum proteins for classifying well-differentiated small intestinal neuroendocrine tumors

PLoS One. 2013 Nov 25;8(11):e81712. doi: 10.1371/journal.pone.0081712. eCollection 2013.


Background: Patients 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 methods: Suspension 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.

Results: A 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.

Conclusions: We 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Proteins / metabolism*
  • Case-Control Studies
  • Cell Differentiation
  • Humans
  • Intestinal Neoplasms / blood
  • Intestinal Neoplasms / classification*
  • Intestinal Neoplasms / pathology
  • Intestine, Small / pathology*
  • Neuroendocrine Tumors / blood
  • Neuroendocrine Tumors / classification*
  • Neuroendocrine Tumors / pathology


  • Blood Proteins

Grant support

This study was funded by grants from Science for Life Laboratory Stockholm (, ProNova VINN Excellence Centre for Protein Technology (VINNOVA) ( and the Knut and Alice Wallenberg Foundation ( The authors certify that no individuals employed or contracted by the funders (other than the named authors) had any role in: study design, data collection and analysis, decision to publish, or preparation of the manuscript.