Background: Duodenopancreatic neuroendocrine tumors (dpNETs) are a frequent manifestation in patients with Multiple Endocrine Neoplasia Type 1 (MEN1), and metastatic dpNET are the primary cause of mortality. We evaluated a humoral response in the form of immunoblobulin (Ig)-bound antigens that are associated with dpNET development and progression in MEN1 patients. Study Design: Proteomic analysis of plasma Ig-bound proteins was performed on a cohort of 42 MEN1patients with dpNET (28 with indolent disease and 14 with liver metastasis) and 14 MEN1 patients without dpNETs. Ingenuity Pathway Analysis and MHC class II binding prediction (NetMHCIIpan) were performed to identify candidate immunogenic antigens and underlying networks. Findings were further compared to proteomics profiles of human pNET tissues. Results: A total of 1117 Ig-bound proteins were identified. Differential analyses revealed 435 Ig-bound antigens to be enriched (exclusive or fold change ≥2.0) in dpNET patients compared to MEN1 patients without dpNETs, of which 130 were highest in those with a dpNET and liver metastasis. Ingenuity Pathway Analysis of the 435 dpNET-associated Ig-bound antigens revealed cancer, endocrine system disorders, and neurological disease as top predicted disease types, and networks centered on B-Cell Receptor and T-Cell Receptor signaling as well as TP53 and TGFB signaling. Intersection with proteomic profiles of human MEN1 pNET tissues revealed 73 overlapping proteins. MHC-II affinity prediction identified SF3B3, ADD2, MDM2, INTS4, and CMTM1 to be encompassing high-binding immunocore sequences. Conclusions: We have uncovered antigenic protein signatures in the form of a humoral response that is associated with development and progression of MEN1-related dpNETs.
Katayama et al. (Wed,) studied this question.