Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair

Robin I Dewalt,1 Kenneth A Kesler,2 Zane T Hammoud,3 LeeAnn Baldridge,4 Eyas M Hattab,4 Shadia I Jalal1,5 1Division of Hematology/Oncology, Department of Medicine, 2Cardiothoracic Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 3Henry Ford Hospital, De...

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Autores principales:	Dewalt RI, Kesler KA, Hammoud ZT, Baldridge L, Hattab EM, Jalal SI
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/1a2b29d239e64ad8a721f92700010ae4
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spelling	oai:doaj.org-article:1a2b29d239e64ad8a721f92700010ae42021-12-02T03:02:10ZGastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair1179-2728https://doaj.org/article/1a2b29d239e64ad8a721f92700010ae42014-02-01T00:00:00Zhttp://www.dovepress.com/gastroesophageal-junction-adenocarcinoma-displays-abnormalities-in-hom-a15822https://doaj.org/toc/1179-2728 Robin I Dewalt,1 Kenneth A Kesler,2 Zane T Hammoud,3 LeeAnn Baldridge,4 Eyas M Hattab,4 Shadia I Jalal1,5 1Division of Hematology/Oncology, Department of Medicine, 2Cardiothoracic Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 3Henry Ford Hospital, Detroit, MI, USA; 4Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 5Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA Objective: Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues. Methods: We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC. Results: We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG. Conclusion: Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC. Keywords: esophageal adenocarcinoma, DNA repair, MUS81/EME1Dewalt RIKesler KAHammoud ZTBaldridge LHattab EMJalal SIDove Medical PressarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENLung Cancer: Targets and Therapy, Vol 2014, Iss default, Pp 11-20 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dewalt RI Kesler KA Hammoud ZT Baldridge L Hattab EM Jalal SI Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
description	Robin I Dewalt,1 Kenneth A Kesler,2 Zane T Hammoud,3 LeeAnn Baldridge,4 Eyas M Hattab,4 Shadia I Jalal1,5 1Division of Hematology/Oncology, Department of Medicine, 2Cardiothoracic Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 3Henry Ford Hospital, Detroit, MI, USA; 4Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 5Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA Objective: Esophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues. Methods: We analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC. Results: We identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG. Conclusion: Our study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC. Keywords: esophageal adenocarcinoma, DNA repair, MUS81/EME1
format	article
author	Dewalt RI Kesler KA Hammoud ZT Baldridge L Hattab EM Jalal SI
author_facet	Dewalt RI Kesler KA Hammoud ZT Baldridge L Hattab EM Jalal SI
author_sort	Dewalt RI
title	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
title_short	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
title_full	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
title_fullStr	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
title_full_unstemmed	Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
title_sort	gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/1a2b29d239e64ad8a721f92700010ae4
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_version_	1718401966579646464

Gastroesophageal junction adenocarcinoma displays abnormalities in homologous recombination and nucleotide excision repair

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