Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors

Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-...

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Main Authors:	Park, Charny, Ha, Sang Yun, Kim, Seung Tae, Kim, Hee Cheol, Heo, Jin Seok, Park, Young Suk, Lauwers, Gregory, Lee, Jeeyun, Kim, Kyoung-Mee
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826187/

id	pubmed-4826187
recordtype	oai_dc
spelling	pubmed-48261872016-05-09 Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors Park, Charny Ha, Sang Yun Kim, Seung Tae Kim, Hee Cheol Heo, Jin Seok Park, Young Suk Lauwers, Gregory Lee, Jeeyun Kim, Kyoung-Mee Research Paper Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients. Impact Journals LLC 2015-12-14 /pmc/articles/PMC4826187/ /pubmed/26684240 http://dx.doi.org/10.18632/oncotarget.6602 Text en Copyright: © 2016 Park et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Park, Charny Ha, Sang Yun Kim, Seung Tae Kim, Hee Cheol Heo, Jin Seok Park, Young Suk Lauwers, Gregory Lee, Jeeyun Kim, Kyoung-Mee
spellingShingle	Park, Charny Ha, Sang Yun Kim, Seung Tae Kim, Hee Cheol Heo, Jin Seok Park, Young Suk Lauwers, Gregory Lee, Jeeyun Kim, Kyoung-Mee Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
author_facet	Park, Charny Ha, Sang Yun Kim, Seung Tae Kim, Hee Cheol Heo, Jin Seok Park, Young Suk Lauwers, Gregory Lee, Jeeyun Kim, Kyoung-Mee
author_sort	Park, Charny
title	Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
title_short	Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
title_full	Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
title_fullStr	Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
title_full_unstemmed	Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors
title_sort	identification of the braf v600e mutation in gastroenteropancreatic neuroendocrine tumors
description	Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826187/
_version_	1613564256830095360

Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors

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