Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma
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Ruchi Shukla Kyle R Upton Martin Muñoz-Lopez Daniel J Gerhardt Malcolm E Fisher Thu Nguyen Paul M Brennan J Kenneth Baillie Agnese Collino Serena Ghisletti Shruti Sinha Fabio Iannelli Enrico Radaelli Alexandre Dos Santos Delphine Rapoud Catherine Guettier Didier Samuel Gioacchino Natoli Piero Carninci Francesca Ciccarelli Jose Luis Garcia-Perez Jamila Faivre Geoffrey J FaulknerAbstract
LINE-1 (L1) retrotransposons are mobile genetic elements comprising ~17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.
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Publisher website (DOI) 10.1016/j.cell.2013.02.032
Europe PubMed Central 23540693
Pubmed 23540693
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