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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer

View ORCID ProfileNikolaos M. R. Lykoskoufis, Evarist Planet, View ORCID ProfileHalit Ongen, View ORCID ProfileDidier Trono, View ORCID ProfileEmmanouil T. Dermitzakis
doi: https://doi.org/10.1101/2021.12.03.471093
Nikolaos M. R. Lykoskoufis
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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  • ORCID record for Nikolaos M. R. Lykoskoufis
  • For correspondence: nikolaos.lykoskoufis@unige.ch emmanouil.dermitzakis@unige.ch
Evarist Planet
4School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
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Halit Ongen
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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Didier Trono
4School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland
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Emmanouil T. Dermitzakis
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
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  • For correspondence: nikolaos.lykoskoufis@unige.ch emmanouil.dermitzakis@unige.ch
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ABSTRACT

Transposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.

Competing Interest Statement

Emmanouil T. Dermitzakis is currently an employee of GSK. The work presented in this manuscript was performed before he joined GSK. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 04, 2021.
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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
Nikolaos M. R. Lykoskoufis, Evarist Planet, Halit Ongen, Didier Trono, Emmanouil T. Dermitzakis
bioRxiv 2021.12.03.471093; doi: https://doi.org/10.1101/2021.12.03.471093
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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
Nikolaos M. R. Lykoskoufis, Evarist Planet, Halit Ongen, Didier Trono, Emmanouil T. Dermitzakis
bioRxiv 2021.12.03.471093; doi: https://doi.org/10.1101/2021.12.03.471093

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