Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

Shukla, Ruchi, Upton, Kyle R., Muñoz-Lopez, Martin, Gerhardt, Daniel J., Fisher, Malcolm E., Thu Nguyen, Brennan, Paul M., Baillie, J. Kenneth, Collino, Agnese, Ghisletti, Serena, Sinha, Shruti, Iannelli, Fabio, Radaelli, Enrico, Dos Santos, Alexandre, Rapoud, Delphine, Guettier, Catherine, Samuel, Didier, Natoli, Gioacchino, Carninci, Piero, Ciccarelli, Francesca D., Luis Garcia-Perez, Jose, Faivre, Jamila and Faulkner, Geoffrey J. (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell, 153 1: 101-111. doi:10.1016/j.cell.2013.02.032

Author Shukla, Ruchi
Upton, Kyle R.
Muñoz-Lopez, Martin
Gerhardt, Daniel J.
Fisher, Malcolm E.
Thu Nguyen
Brennan, Paul M.
Baillie, J. Kenneth
Collino, Agnese
Ghisletti, Serena
Sinha, Shruti
Iannelli, Fabio
Radaelli, Enrico
Dos Santos, Alexandre
Rapoud, Delphine
Guettier, Catherine
Samuel, Didier
Natoli, Gioacchino
Carninci, Piero
Ciccarelli, Francesca D.
Luis Garcia-Perez, Jose
Faivre, Jamila
Faulkner, Geoffrey J.
Title Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
Publication date 2013-03-28
Sub-type Article (original research)
DOI 10.1016/j.cell.2013.02.032
Volume 153
Issue 1
Start page 101
End page 111
Total pages 11
Place of publication Cambridge, MA United States
Publisher Cell Press
Collection year 2014
Language eng
Formatted 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.

Highlights ► L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) ► Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling ► L1 mobilization in tumor cells accelerates transformation of the HCC genome ► A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18
Keyword Hepatitis-B-virus
Human genome
Line-1 retrotransposition
L1 retrotransposition
Somatic retrotransposition
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
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