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

doi:10.3892/mco.2017.1194

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

Authors:
- Heike Loeser
- Dirk Waldschmidt
- Fabian Kuetting
- Carina Heydt
- Thomas Zander
- Patrick Plum
- Hakan Alakus
- Reinhard Buettner
- Alexander Quaas
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Affiliations: Institute of Pathology, University of Cologne, Gastrointestinal Cancer Group Cologne, D-50937 Cologne, Germany, Department of Gastroenterology and Hepatology, University of Cologne, Gastrointestinal Cancer Group Cologne, D-50937 Cologne, Germany, Department of Oncology and Hematology, University of Cologne, Gastrointestinal Cancer Group Cologne, D-50937 Cologne, Germany, Department of Visceral Surgery, University of Cologne, Gastrointestinal Cancer Group Cologne, D-50937 Cologne, Germany
Published online on: March 14, 2017 https://doi.org/10.3892/mco.2017.1194
Pages: 639-642
Copyright: © Loeser et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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