Abstract
BackgroundGenetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA).ResultsSignificant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression.ConclusionsThe data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.
Highlights
Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences
Methylation analysis focused on a region covering the three prime repair exonuclease 2 (TREX2)-related CpG island (Fig. 1b, upper panel) as DNA quality and amount were limited by the available formalin-fixed paraffin-embedded (FFPE) tissue sections
Differential DNA methylation of TREX2 is associated with survival in laryngeal cancer Based on the functional link of DNA methylation and gene expression, we investigated the possible association of TREX2 differentially methylated region (DMR) methylation with overall survival in our laryngeal cancer cohort
Summary
Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). We here quantified DNA methylation at the DNA repair gene three prime repair exonuclease 2 (TREX2) in tumor tissue compared to adjacent normal tissue in an independent, population-based case-control study of laryngeal cancer patients from Germany [3, 7]. We observed loss of DNA methylation at a TREX2 intragenic gene locus in laryngeal cancer, colorectal cancer, and further cancer studies from The Cancer Genome Atlas (TCGA). Epigenetic deregulation of TREX2 expression was observed in multiple cancers This highlights its potential involvement in fundamental cellular responses to tumorigenesis
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