Cargando…

ODP300 c-MET expression in MEN1-associated neuroendocrine tumors

 : Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most co...

Descripción completa

Detalles Bibliográficos
Autores principales: Ghosh, Raisa, Lee, Maya, Tora, Rana, Welch, James, Parekh, Vaishali I, del Rivero, Jaydira, Simonds, William F, Weinstein, Lee Scott, Blau, Jenny E, Agarwal, Sunita K, Jha, Smita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627069/
http://dx.doi.org/10.1210/jendso/bvac150.1010
_version_ 1784822882743877632
author Ghosh, Raisa
Lee, Maya
Tora, Rana
Welch, James
Parekh, Vaishali I
del Rivero, Jaydira
Simonds, William F
Weinstein, Lee Scott
Blau, Jenny E
Agarwal, Sunita K
Jha, Smita
author_facet Ghosh, Raisa
Lee, Maya
Tora, Rana
Welch, James
Parekh, Vaishali I
del Rivero, Jaydira
Simonds, William F
Weinstein, Lee Scott
Blau, Jenny E
Agarwal, Sunita K
Jha, Smita
author_sort Ghosh, Raisa
collection PubMed
description  : Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival. While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc.) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs. METHODS: We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression. RESULTS: Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged. CONCLUSION: Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.
format Online
Article
Text
id pubmed-9627069
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-96270692022-11-03 ODP300 c-MET expression in MEN1-associated neuroendocrine tumors Ghosh, Raisa Lee, Maya Tora, Rana Welch, James Parekh, Vaishali I del Rivero, Jaydira Simonds, William F Weinstein, Lee Scott Blau, Jenny E Agarwal, Sunita K Jha, Smita J Endocr Soc Neuroendocrinology and Pituitary  : Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival. While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc.) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs. METHODS: We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression. RESULTS: Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged. CONCLUSION: Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m. Oxford University Press 2022-11-01 /pmc/articles/PMC9627069/ http://dx.doi.org/10.1210/jendso/bvac150.1010 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Neuroendocrinology and Pituitary
Ghosh, Raisa
Lee, Maya
Tora, Rana
Welch, James
Parekh, Vaishali I
del Rivero, Jaydira
Simonds, William F
Weinstein, Lee Scott
Blau, Jenny E
Agarwal, Sunita K
Jha, Smita
ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title_full ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title_fullStr ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title_full_unstemmed ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title_short ODP300 c-MET expression in MEN1-associated neuroendocrine tumors
title_sort odp300 c-met expression in men1-associated neuroendocrine tumors
topic Neuroendocrinology and Pituitary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627069/
http://dx.doi.org/10.1210/jendso/bvac150.1010
work_keys_str_mv AT ghoshraisa odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT leemaya odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT torarana odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT welchjames odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT parekhvaishalii odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT delriverojaydira odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT simondswilliamf odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT weinsteinleescott odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT blaujennye odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT agarwalsunitak odp300cmetexpressioninmen1associatedneuroendocrinetumors
AT jhasmita odp300cmetexpressioninmen1associatedneuroendocrinetumors