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 language | English |
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Pages (from-to) | 101-11 |
Number of pages | 11 |
Journal | Cell |
Volume | 153 |
Issue number | 1 |
DOIs | |
Publication status | Published - 28 Mar 2013 |
Keywords
- Adult
- Aged
- Animals
- Carcinoma, Hepatocellular
- Cell Line, Tumor
- Cell Transformation, Neoplastic
- DNA Mutational Analysis
- Female
- Genes, Tumor Suppressor
- Humans
- Liver Neoplasms
- Long Interspersed Nucleotide Elements
- Male
- Mice
- Middle Aged
- Mutagenesis, Insertional
- P-Glycoproteins
- Repressor Proteins
- Tumor Suppressor Proteins