1. Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma
- Author
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Shruti Sinha, Agnese Collino, Daniel J. Gerhardt, Geoffrey J. Faulkner, Jose L. Garcia-Perez, Francesca D. Ciccarelli, Piero Carninci, Jamila Faivre, Alexandre Dos Santos, Serena Ghisletti, Gioacchino Natoli, Thu T. Nguyen, Catherine Guettier, Martin Muñoz-Lopez, Ruchi Shukla, Delphine Rapoud, Fabio Iannelli, J Kenneth Baillie, Malcolm E. Fisher, Kyle R. Upton, Didier Samuel, Paul Brennan, and Enrico Radaelli
- Subjects
Male ,HEPATITIS-B-VIRUS ,DNA Mutational Analysis ,Retrotransposon ,medicine.disease_cause ,Germline ,COLORECTAL-CANCER ,law.invention ,Mice ,0302 clinical medicine ,MAMMALIAN-CELLS ,law ,HUMAN GENOME ,Genes, Tumor Suppressor ,TUMOR-SUPPRESSOR ,0303 health sciences ,Liver Neoplasms ,Wnt signaling pathway ,Middle Aged ,SOMATIC RETROTRANSPOSITION ,3. Good health ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Female ,Adult ,ATP Binding Cassette Transporter, Subfamily B ,Carcinoma, Hepatocellular ,L1 RETROTRANSPOSITION ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Enhancer ,Aged ,030304 developmental biology ,IDENTIFICATION ,Oncogene ,Biochemistry, Genetics and Molecular Biology(all) ,Tumor Suppressor Proteins ,LINE-1 RETROTRANSPOSITION ,Cancer ,medicine.disease ,GENE ,Molecular biology ,Repressor Proteins ,Mutagenesis, Insertional ,Long Interspersed Nucleotide Elements ,Cancer research ,Suppressor ,Carcinogenesis - Abstract
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.
- Published
- 2013
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