Open AccessA Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression
Author(s) -
Johannes F. Fahrmann,
Amanda R. Wasylishen,
Carolina R. C. Pieterman,
Ehsan Irajizad,
Jody Vykoukal,
Eunice Murage,
Ranran Wu,
Jennifer B. Dennison,
H. N. Gopala Krishna,
Christine B. Peterson,
Guillermina Lozano,
Hua Zhao,
KimAnh Do,
Daniel M. Halperin,
Sunita Agarwal,
Jenny Blau,
Jaydira Del Rivero,
Naris Nilubol,
Mary Walter,
James Welch,
Lee S. Weinstein,
Menno R. Vriens,
Rachel S. van Leeuwaarde,
Mark J C van Treijen,
Gerlof D. Valk,
Nancy D. Perrier,
Samir Hanash
Publication year - 2021
Publication title -
the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.206
H-Index - 353
eISSN - 1945-7197
pISSN - 0021-972X
DOI - 10.1210/clinem/dgab554
Subject(s) - men1 , signature (topology) , polyamine , neuroendocrine tumors , cancer research , medicine , biology , mathematics , genetics , endocrine system , geometry , hormone
Context Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types. Objective We hypothesized that MEN1-dpNET–related disease progression is associated with elevated levels of circulating polyamines. Methods Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs [patients] and 64 with either indolent dpNETs or no dpNETs [controls]). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression. Results A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression. Conclusion Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.