title: Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors.
abstract: BACKGROUND
  Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs.
  
  
  RESULTS
  A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples.
  
  
  CONCLUSIONS
  Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.
authors.affiliation: Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden.
authors.forename: Tao
authors.initials: T
authors.lastname: Cui
authors.forename: Monica
authors.initials: M
authors.lastname: Hurtig
authors.forename: Graciela
authors.initials: G
authors.lastname: Elgue
authors.forename: Su-Chen
authors.initials: SC
authors.lastname: Li
authors.forename: Giulia
authors.initials: G
authors.lastname: Veronesi
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alimohammadi
authors.forename: Kjell
authors.initials: K
authors.lastname: Öberg
authors.forename: Valeria
authors.initials: V
authors.lastname: Giandomenico
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry*; D001323:Autoantibodies / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000097:blood*; D053379:Chromogranin A / Q000737:chemistry; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007414:Intestinal Neoplasms / Q000097:blood* / Q000175:diagnosis*; D007421:Intestine, Small / Q000473:pathology*; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis*; D012008:Recurrence; D012680:Sensitivity and Specificity; D055752:Small Cell Lung Carcinoma / Q000175:diagnosis* / Q000473:pathology*
chemical_list: D000951:Antigens, Neoplasm; D001323:Autoantibodies; D014408:Biomarkers, Tumor; D053379:Chromogranin A; C119249:Ma2 antigen; D009419:Nerve Tissue Proteins