Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

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 D. CiccarelliJose Luis Garcia-Perez, Jamila Faivre, Geoffrey J. Faulkner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)101-111
Number of pages11
JournalCell
Volume153
Issue number1
DOIs
Publication statusPublished - Mar 28 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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