Abstract 3364: DNA methylation loss at an enhancer site of the DNA repair gene TREX2 is an epigenetic feature in multiple cancers

Abstract

The onset of numerous cancers is strongly associated with exposure to genotoxic agents and is counteracted by cellular DNA repair mechanisms. However, the tumorigenic potential of genotoxic carcinogens varies widely among individuals. It is still uncertain which genetic and epigenetic traits shape cancer onset and progression in the general population. While genetic aberrations in DNA repair genes have been linked to cancer risk, less is known about the importance of epigenetics for the regulation of these genes. In order to identify DNA methylation alterations in laryngeal cancer we carried out targeted DNA methylation analysis at single CpG sites via mass spectrometry. We focused our analysis on five DNA repair-associated gene loci previously found to be altered in head and neck squamous cell carcinoma. We report loss of DNA methylation at the three prime repair exonuclease 2 (TREX2) gene locus in laryngeal cancer (n=161) and adjacent normal tissue (n=58) samples of patients from a German population-based case-control study. Following screening of tumor tissues from Chinese colorectal cancer patients as well as previously published data from the Cancer Genome Atlas (TCGA), we identified TREX2 methylation loss as a frequent trait in multiple cancers. We further characterized the regulatory activity of the affected TREX2 site using chromatin immunoprecipitation and luciferase reporter assays in cell models from different tumor types. Differential TREX2 methylation affects a CCAAT/enhancer binding protein alpha (CEBPA) binding site serving as a gene enhancer which drives the expression of TREX2 from a previously uncharacterized gene promoter. We also observed a strong association between TREX2 methylation and TREX2 protein expression determined via immunohistochemistry in laryngeal tumors. Finally, we found a significant association between overall survival and loss of TREX2 methylation in laryngeal cancer, with TREX2 methylation loss being a protective factor. Our findings highlight a profound regulatory role of epigenetic mechanisms for TREX2 in tumors, and underline the usefulness of TREX2 DNA methylation as a biomarker for patient stratification. Citation Format: Christoph Weigel, Jittiporn Chaisaingmongkol, Christine Kuhmann, Irene Santi, Volker Winkler, Olga Bogatyrova, Justo L. Bermejo, Tsun L. Chan, Felix Lasitschka, Manfred H. Bohrer, Alexander Marx, Frank Autschbach, Roland Heyni-von Haußen, Gerhard Dyckhoff, Klaus-Wolfgang Delank, Karl Hoermann, Burkard M. Lippert, Gerald Baier, Andreas Dietz, Christopher C. Oakes, Christoph Plass, Heiko Becher, Peter Schmezer, Heribert Ramroth, Odilia Popanda. DNA methylation loss at an enhancer site of the DNA repair gene TREX2 is an epigenetic feature in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3364. doi:10.1158/1538-7445.AM2017-3364