Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression

Authors

Johannes F Fahrmann
Amanda R Wasylishen
Carolina R C Pieterman
Ehsan Irajizad
Jody Vykoukal
Ranran Wu
Jennifer B Dennison
Christine B Peterson
Hua Zhao
Kim-Anh Do
Daniel M Halperin
Sunita K Agarwal
Jenny E Blau
Smita Jha
Jaydira Del Rivero
Naris Nilubol
Mary F Walter
James M Welch
Lee S Weinstein
Menno R Vriens
Rachel S van Leeuwaarde
Mark J C van Treijen
Gerlof D Valk
Nancy D Perrier
Samir M Hanash
Hiroyuki Katayama

Publication Date

11-17-2023

Journal

The Journal of Clinical Endocrinology and Metabolism

Abstract

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression.

EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl).

RESULTS: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice.

CONCLUSIONS: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

Keywords

Animals, Humans, Mice, Disease Progression, Multiple Endocrine Neoplasia Type 1, Neuroendocrine Tumors, Pancreatic Neoplasms, Proteomics, Proto-Oncogene Proteins

Comments

PMID: 37307230