First Author | Shukla R | Year | 2013 |
Journal | Cell | Volume | 153 |
Issue | 1 | Pages | 101-11 |
PubMed ID | 23540693 | Mgi Jnum | J:197248 |
Mgi Id | MGI:5491969 | Doi | 10.1016/j.cell.2013.02.032 |
Citation | Shukla R, et al. (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153(1):101-11 |
abstractText | 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 beta-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. |