Johannes F Fahrmann1, Amanda R Wasylishen2, Carolina R C Pieterman3, Ehsan Irajizad1,4, Jody Vykoukal1, Eunice Murage1, Ranran Wu1, Jennifer B Dennison1, Hansini Krishna1, Christine B Peterson4, Guillermina Lozano2, Hua Zhao5,6, Kim-Anh Do4, Daniel M Halperin7, Sunita K Agarwal8, Jenny E Blau8, Jaydira Del Rivero9, Naris Nilubol10, Mary F Walter11, James M Welch8, Lee S Weinstein8, Menno R Vriens12,13, Rachel S van Leeuwaarde13,14, Mark J C van Treijen13,14, Gerlof D Valk13,14, Nancy D Perrier3, Samir M Hanash1. 1. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 2. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 3. Department of Surgical Oncology, Section of Surgical Endocrinology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 5. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 6. Department of Family Medicine and Population Health, Virginia Commonwealth University, Richmond, Virgina, USA. 7. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 8. Metabolic Diseases Branch, the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 9. Developmental Therapeutics Branch, the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 10. Surgical Oncology Program, the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 11. Core for Clinical Laboratory Services, the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. 12. Department of Surgical Oncology and Endocrine Surgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands. 13. Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute Amsterdam, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands. 14. Department of Endocrine Oncology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Abstract
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.
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.
Authors: Paul A Harris; Robert Taylor; Robert Thielke; Jonathon Payne; Nathaniel Gonzalez; Jose G Conde Journal: J Biomed Inform Date: 2008-09-30 Impact factor: 6.317
Authors: Carolina R C Pieterman; Joanne M de Laat; Jos W R Twisk; Rachel S van Leeuwaarde; Wouter W de Herder; Koen M A Dreijerink; Ad R M M Hermus; Olaf M Dekkers; Anouk N A van der Horst-Schrivers; Madeleine L Drent; Peter H Bisschop; Bastiaan Havekes; Inne H M Borel Rinkes; Menno R Vriens; Gerlof D Valk Journal: J Clin Endocrinol Metab Date: 2017-10-01 Impact factor: 5.958
Authors: Sjoerd Nell; Helena M Verkooijen; Carolina R C Pieterman; Wouter W de Herder; Ad R Hermus; Olaf M Dekkers; Anouk N van der Horst-Schrivers; Madeleine L Drent; Peter H Bisschop; Bas Havekes; Inne H M Borel Rinkes; Menno R Vriens; Gerlof D Valk Journal: Ann Surg Date: 2018-06 Impact factor: 12.969
Authors: Ahmad L Subhi; Baiqing Tang; Binaifer R Balsara; Deborah A Altomare; Joseph R Testa; Harry S Cooper; John P Hoffman; Neal J Meropol; Warren D Kruger Journal: Clin Cancer Res Date: 2004-11-01 Impact factor: 12.531
Authors: H-C Jennifer Shen; Kris Ylaya; Klaus Pechhold; Arianne Wilson; Asha Adem; Stephen M Hewitt; Steven K Libutti Journal: Endocrinology Date: 2010-06-16 Impact factor: 4.736
Authors: Joanne M de Laat; Rob B van der Luijt; Carolina R C Pieterman; Maria P Oostveen; Ad R Hermus; Olaf M Dekkers; Wouter W de Herder; Anouk N van der Horst-Schrivers; Madeleine L Drent; Peter H Bisschop; Bas Havekes; Menno R Vriens; Gerlof D Valk Journal: BMC Med Date: 2016-11-15 Impact factor: 8.775
Authors: Johannes F Fahrmann; Amanda R Wasylishen; Carolina R C Pieterman; Ehsan Irajizad; Jody Vykoukal; Eunice Murage; Ranran Wu; Jennifer B Dennison; Hansini Krishna; Christine B Peterson; Guillermina Lozano; Hua Zhao; Kim-Anh Do; Daniel M Halperin; Sunita K Agarwal; Jenny E Blau; 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 Journal: J Clin Endocrinol Metab Date: 2021-11-19 Impact factor: 6.134
Authors: Jason B Liu; Jinman Cai; Mashaal Dhir; Alessandro Paniccia; Amer H Zureikat; Kimberly M Ramonell; Kelly L McCoy; Sally E Carty; Linwah Yip Journal: Ann Surg Oncol Date: 2022-08-13 Impact factor: 4.339
Authors: Ehsan Irajizad; Ranran Wu; Jody Vykoukal; Eunice Murage; Rachelle Spencer; Jennifer B Dennison; Stacy Moulder; Elizabeth Ravenberg; Bora Lim; Jennifer Litton; Debu Tripathym; Vicente Valero; Senthil Damodaran; Gaiane M Rauch; Beatriz Adrada; Rosalind Candelaria; Jason B White; Abenaa Brewster; Banu Arun; James P Long; Kim Anh Do; Sam Hanash; Johannes F Fahrmann Journal: Front Artif Intell Date: 2022-08-11
Authors: Johannes F Fahrmann; Amanda R Wasylishen; Carolina R C Pieterman; Ehsan Irajizad; Jody Vykoukal; Eunice Murage; Ranran Wu; Jennifer B Dennison; Hansini Krishna; Christine B Peterson; Guillermina Lozano; Hua Zhao; Kim-Anh Do; Daniel M Halperin; Sunita K Agarwal; Jenny E Blau; 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 Journal: J Clin Endocrinol Metab Date: 2021-11-19 Impact factor: 6.134