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Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target

Adenocarcinoma of the pancreas has a poor prognosis. At present, no relevant personalized targets have been identified. Sequencing studies have implicated gene alterations of disruptor of telomeric silencing 1 like histone lysine methyltransferase (DOT1L) in pancreatic adenocarcinoma. DOT1L is part...

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Autores principales: Loeser, Heike, Waldschmidt, Dirk, Kuetting, Fabian, Heydt, Carina, Zander, Thomas, Plum, Patrick, Alakus, Hakan, Buettner, Reinhard, Quaas, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432215/
https://www.ncbi.nlm.nih.gov/pubmed/28529740
http://dx.doi.org/10.3892/mco.2017.1194
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author Loeser, Heike
Waldschmidt, Dirk
Kuetting, Fabian
Heydt, Carina
Zander, Thomas
Plum, Patrick
Alakus, Hakan
Buettner, Reinhard
Quaas, Alexander
author_facet Loeser, Heike
Waldschmidt, Dirk
Kuetting, Fabian
Heydt, Carina
Zander, Thomas
Plum, Patrick
Alakus, Hakan
Buettner, Reinhard
Quaas, Alexander
author_sort Loeser, Heike
collection PubMed
description Adenocarcinoma of the pancreas has a poor prognosis. At present, no relevant personalized targets have been identified. Sequencing studies have implicated gene alterations of disruptor of telomeric silencing 1 like histone lysine methyltransferase (DOT1L) in pancreatic adenocarcinoma. DOT1L is part of the histone modification system and catalyzes methylation of H3K79, which is crucial in cell signaling and DNA damage repair. DOT1L is considered to be a target of therapy in mixed lineage leukemia gene-deficient leukemia cases and a potential target in breast carcinoma. The frequencies and importance of DOT1L copy-number variations and their specific correlation with protein expression in adenocarcinoma of the pancreas have yet to be investigated. In the present study, tissue microarrays of 230 resected pancreatic adenocarcinoma cases were constructed. The tumor tissue was analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry. In total, 10/225 carcinoma cases (4.4%) analyzed by immunohistochemistry demonstrated intense nuclear protein expression of DOT1L and in 9/224 tumors analyzed using FISH (4.0%), copy-number variations (CNV) were detectable. No DOT1L amplification was detected in the carcinoma cohort. To the best of our knowledge, the present study describes for the first time the frequency of CNV of DOT1L using the gold standard fluorescence in situ hybridization (FISH) and their specific correlation to the protein expression in adenocarcinomas of the pancreas. Although the positive cases by immunohistochemistry and copy-number variations by FISH were not congruent with each other, the data suggest a potential role for DOT1L in a small subset of pancreatic cancer cases. The significance of the two analysis methods concerning their druggability in pancreatic adenocarcinoma requires further studies.
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spelling pubmed-54322152017-05-19 Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target Loeser, Heike Waldschmidt, Dirk Kuetting, Fabian Heydt, Carina Zander, Thomas Plum, Patrick Alakus, Hakan Buettner, Reinhard Quaas, Alexander Mol Clin Oncol Articles Adenocarcinoma of the pancreas has a poor prognosis. At present, no relevant personalized targets have been identified. Sequencing studies have implicated gene alterations of disruptor of telomeric silencing 1 like histone lysine methyltransferase (DOT1L) in pancreatic adenocarcinoma. DOT1L is part of the histone modification system and catalyzes methylation of H3K79, which is crucial in cell signaling and DNA damage repair. DOT1L is considered to be a target of therapy in mixed lineage leukemia gene-deficient leukemia cases and a potential target in breast carcinoma. The frequencies and importance of DOT1L copy-number variations and their specific correlation with protein expression in adenocarcinoma of the pancreas have yet to be investigated. In the present study, tissue microarrays of 230 resected pancreatic adenocarcinoma cases were constructed. The tumor tissue was analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry. In total, 10/225 carcinoma cases (4.4%) analyzed by immunohistochemistry demonstrated intense nuclear protein expression of DOT1L and in 9/224 tumors analyzed using FISH (4.0%), copy-number variations (CNV) were detectable. No DOT1L amplification was detected in the carcinoma cohort. To the best of our knowledge, the present study describes for the first time the frequency of CNV of DOT1L using the gold standard fluorescence in situ hybridization (FISH) and their specific correlation to the protein expression in adenocarcinomas of the pancreas. Although the positive cases by immunohistochemistry and copy-number variations by FISH were not congruent with each other, the data suggest a potential role for DOT1L in a small subset of pancreatic cancer cases. The significance of the two analysis methods concerning their druggability in pancreatic adenocarcinoma requires further studies. D.A. Spandidos 2017-05 2017-03-14 /pmc/articles/PMC5432215/ /pubmed/28529740 http://dx.doi.org/10.3892/mco.2017.1194 Text en Copyright: © Loeser et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Loeser, Heike
Waldschmidt, Dirk
Kuetting, Fabian
Heydt, Carina
Zander, Thomas
Plum, Patrick
Alakus, Hakan
Buettner, Reinhard
Quaas, Alexander
Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title_full Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title_fullStr Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title_full_unstemmed Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title_short Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target
title_sort copy-number variation and protein expression of dot1l in pancreatic adenocarcinoma as a potential drug target
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432215/
https://www.ncbi.nlm.nih.gov/pubmed/28529740
http://dx.doi.org/10.3892/mco.2017.1194
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