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Shukla, Ruchi; Upton, Kyle R.; Muñoz-Lopez, Martin; Gerhardt, Daniel J.; Fisher, Malcolm E.; Nguyen, Thu; Brennan, Paul M.; Baillie, J. Kenneth; Collino, Agnese; Ghisletti, Serena; Sinha, Shruti; Iannelli, Fabio; Radaelli, Enrico; Dos Santos, Alexandre; Rapoud, Delphine; Guettier, Catherine; Samuel, Didier; Natoli, Gioacchino; Carninci, Piero; Ciccarelli, Francesca D.; Garcia-Perez, Jose Luis; Faivre, Jamila; Faulkner, Geoffrey J.
Cell, 03/2013, Letnik: 153, Številka: 1Journal Article
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. Display omitted ► L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) ► Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling ► L1 mobilization in tumor cells accelerates transformation of the HCC genome ► A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18 L1 retrotransposons, which are widespread in the human genome, can mobilize and activate oncogenes in the livers of individuals infected with the hepatitis B or hepatitis C virus, promoting the development and growth of hepatocellular carcinoma. Genes identified by the L1 insertions present new options for cancer screening and intervention.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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