Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

Summary 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 m utated in c olorectal c ancers ( MCC ). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, s uppression of t umorigenicity 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.