Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

Ruchi Shukla, Kyle R Upton, Martin Muñoz-Lopez, Daniel J Gerhardt, Malcolm E Fisher, Thu Nguyen, Paul M Brennan, J Kenneth 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 CiccarelliJose Luis Garcia-Perez, Jamila Faivre, Geoffrey J Faulkner

    Research output: Contribution to journalArticlepeer-review

    300 Citations (Scopus)

    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 languageEnglish
    Pages (from-to)101-11
    Number of pages11
    JournalCell
    Volume153
    Issue number1
    DOIs
    Publication statusPublished - 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

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