Author/Authors :
Ruchi Shukla، نويسنده , , Kyle R. Upton، نويسنده , , Martin Mu?oz-Lopez، نويسنده , , Daniel J. Gerhardt، نويسنده , , Malcolm E. Fisher، نويسنده , , Thu Nguyen، نويسنده , , Paul M. Brennan، نويسنده , , J. Kenneth Baillie، نويسنده , , Agnese Collino، نويسنده , , Serena Ghisletti، نويسنده , , Shruti Sinha، نويسنده , , Fabio Iannelli، نويسنده , , Enrico Radaelli، نويسنده , , Pierre Alexandre dos Santos، نويسنده , , Delphine Rapoud، نويسنده , , Catherine Guettier، نويسنده , , Didier Samuel، نويسنده , , Gioacchino Natoli، نويسنده , , Piero Carninci، نويسنده , , Francesca D. Ciccarelli، نويسنده , , et al.، نويسنده ,
Abstract :
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.
