Journal
CELL
Volume 153, Issue 1, Pages 101-111Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.02.032
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Funding
- European Union's Seventh Framework Programme (FP7) underpinning the MODHEP consortium [259743]
- Wellcome Trust Clinical Fellowships through the Edinburgh Clinical Academic Track (ECAT) [090385/Z/09/Z, 090386/Z/09/Z]
- Howard Hughes Medical Institute [IECS-55007420]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Association pour la Recherche contre le Cancer [ARC 4866]
- Institut National du Cancer (INCa PAIR-CHC)
- New Investigator Award from the British BBSRC [BB/H005935/1]
- C.J. Martin Overseas Based Biomedical Fellowship from the Australian NHMRC [575585]
- [FP7-PEOPLE-2007-4-3-IRG]
- [CICE-FEDER-P09-CTS-4980]
- [PeS-FEDER-PI-002]
- [FIS-FEDER-PI11/01489]
- BBSRC [BB/I024801/1, BB/H005935/1, BBS/E/D/20310000] Funding Source: UKRI
- MRC [MR/K001744/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H005935/1, BB/I024801/1, BBS/E/D/20310000] Funding Source: researchfish
- Medical Research Council [MR/K001744/1] Funding Source: researchfish
- Wellcome Trust [090386/Z/09/Z, 090385/Z/09/Z] Funding Source: Wellcome Trust
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LINE-1 (L1) retrotransposons are mobile genetic elements comprising similar to 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.
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