Ruchi Shukla, Kyle R Upton, Martin Mu~noz-Lopez, Daniel J Gerhardt, Malcolm E Fisher, Thu Nguyen, Paul M Brennan, Kenneth J 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 Ciccarelli, Jose Luis Garcia-Perez, Jamila Faivre, Geoffrey J Faulkner: Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. In: Cell, 153 (1), pp. 101–111, 2013.

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 $beta$-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.

BibTeX (Download)

@article{Shukla2013-dp,
title = {Endogenous retrotransposition activates oncogenic pathways in  hepatocellular carcinoma},
author = {Ruchi Shukla and Kyle R Upton and Martin Mu{~n}oz-Lopez and Daniel J Gerhardt and Malcolm E Fisher and Thu Nguyen and Paul M Brennan and Kenneth J Baillie and Agnese Collino and Serena Ghisletti and Shruti Sinha and Fabio Iannelli and Enrico Radaelli and Alexandre Dos Santos and Delphine Rapoud and Catherine Guettier and Didier Samuel and Gioacchino Natoli and Piero Carninci and Francesca D Ciccarelli and Jose Luis Garcia-Perez and Jamila Faivre and Geoffrey J Faulkner},
url = {http://dx.doi.org/10.1016/j.cell.2013.02.032},
year  = {2013},
date = {2013-01-01},
journal = {Cell},
volume = {153},
number = {1},
pages = {101--111},
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 $beta$-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.},
keywords = {Faulknerlab, Major_Publication},
pubstate = {published},
tppubtype = {article}
}