Paraneoplastic Antigen Ma2 Autoantibodies as Specific Blood Biomarkers for Detection of Early Recurrence of Small Intestine Neuroendocrine Tumors

Abstract

BackgroundSmall 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.Methodology/Principal FindingsA 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.ConclusionHere 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.

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

“…Other examples include secretion, e.g. PNMA2 as well as somatostatin receptor expression, both of which have been described in NETs (Reubi et al 2001, Cui et al 2010.…”

“…Captured by gene co-expression networks from tissue and blood transcriptome databases (Modlin et al 2013a, these include biologically relevant transcripts involved in NET proliferation, signaling and secretion (Wulbrand et al 1998, Kidd et al 2006, Karhoff et al 2007, Drozdov et al 2009, Cui et al 2010, Muscarella et al 2011 as well as genes reported to have a defined association with tumor initiation and metastasis (Hogarty et al 2008, Kim et al 2008, Miretti et al 2008, Naik et al 2009, Bralten et al 2010. As such, they overall provide 'omic' information.…”

Bacterial production and purification of immunoreactive paraneoplastic neurological syndrome autoantigen Ma2

“…In men younger than 50 years, anti-Ma2 encephalitis is almost always associated with testicular germ cell tumors that can remain undiscovered for years [19]. In addition, anti-Ma2 antibodies can also be found in patients with small intestine neuroendocrine tumors, small cell lung cancer, breast cancer, Hodgkin's lymphoma and thymoma [3,19,20].…”

“…More precisely, it has been described that Ma2 shows nuclear and cytoplasmic distribution in neurons of the brain, spinal cord, dorsal root ganglia, intestinal autonomic neurons and adrenal medullary ganglia [2]. PNS auto antigen Ma2 is expressed by most small intestine neuroendocrine tumors, whereby about 50% of those tumor patients develop anti-Ma2 autoantibodies [3].…”

Improving the Diagnosis and Management of Neuroendocrine Tumors: Utilizing New Advances in Biomarker and Molecular Imaging Science

“…A novel indirect ELISA was set up to detect PNMA2 autoantibodies in serum and plasma samples from 124 patients with NET of the small intestine at different stages of disease. Among patients with a primary tumor (n = 36), lymph node metastasis (n = 38) and liver metastasis (n = 50), the novel PNMA2 autoantibody ELISA showed high sensitivity, specificity and accuracy, with receiver-operating characteristics curve analysis demonstrating an area of 0.734 for liver metastasis, 0.802 for lymph node metastasis and 0.816 for a primary NET of the small intestine [32]. As such, the assay was able to stratify between patients with a primary NET and healthy controls (area under the curve >0.730).…”