Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma

Abstract Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obt...

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Autores principales:	T. P. MacGregor, R. Carter, R. S. Gillies, J. M. Findlay, C. Kartsonaki, F. Castro-Giner, N. Sahgal, L. M. Wang, R. Chetty, N. D. Maynard, J. B. Cazier, F. Buffa, P. J. McHugh, I. Tomlinson, M. R. Middleton, R. A. Sharma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d0870d7f2504c6cb7bd6fa3f5792e59
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spelling	oai:doaj.org-article:4d0870d7f2504c6cb7bd6fa3f5792e592021-12-02T12:33:00ZTranslational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma10.1038/s41598-018-24232-22045-2322https://doaj.org/article/4d0870d7f2504c6cb7bd6fa3f5792e592018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24232-2https://doaj.org/toc/2045-2322Abstract Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.T. P. MacGregorR. CarterR. S. GilliesJ. M. FindlayC. KartsonakiF. Castro-GinerN. SahgalL. M. WangR. ChettyN. D. MaynardJ. B. CazierF. BuffaP. J. McHughI. TomlinsonM. R. MiddletonR. A. SharmaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q T. P. MacGregor R. Carter R. S. Gillies J. M. Findlay C. Kartsonaki F. Castro-Giner N. Sahgal L. M. Wang R. Chetty N. D. Maynard J. B. Cazier F. Buffa P. J. McHugh I. Tomlinson M. R. Middleton R. A. Sharma Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
description	Abstract Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.
format	article
author	T. P. MacGregor R. Carter R. S. Gillies J. M. Findlay C. Kartsonaki F. Castro-Giner N. Sahgal L. M. Wang R. Chetty N. D. Maynard J. B. Cazier F. Buffa P. J. McHugh I. Tomlinson M. R. Middleton R. A. Sharma
author_facet	T. P. MacGregor R. Carter R. S. Gillies J. M. Findlay C. Kartsonaki F. Castro-Giner N. Sahgal L. M. Wang R. Chetty N. D. Maynard J. B. Cazier F. Buffa P. J. McHugh I. Tomlinson M. R. Middleton R. A. Sharma
author_sort	T. P. MacGregor
title	Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
title_short	Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
title_full	Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
title_fullStr	Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
title_full_unstemmed	Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
title_sort	translational study identifies xpf and mus81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/4d0870d7f2504c6cb7bd6fa3f5792e59
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Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma

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