RT Journal Article
SR Electronic
T1 Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.03.471093
DO 10.1101/2021.12.03.471093
A1 Nikolaos M. R. Lykoskoufis
A1 Evarist Planet
A1 Halit Ongen
A1 Didier Trono
A1 Emmanouil T. Dermitzakis
YR 2021
UL http://biorxiv.org/content/early/2021/12/04/2021.12.03.471093.abstract
AB 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 StatementEmmanouil 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.