title: Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
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.
authors.affiliation: Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, UK.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Upton
authors.forename: Martin
authors.initials: M
authors.lastname: Muñoz-Lopez
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gerhardt
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Fisher
authors.forename: Thu
authors.initials: T
authors.lastname: Nguyen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Brennan
authors.forename: J Kenneth
authors.initials: JK
authors.lastname: Baillie
authors.forename: Agnese
authors.initials: A
authors.lastname: Collino
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.forename: Shruti
authors.initials: S
authors.lastname: Sinha
authors.forename: Fabio
authors.initials: F
authors.lastname: Iannelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dos Santos
authors.forename: Delphine
authors.initials: D
authors.lastname: Rapoud
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Francesca D
authors.initials: FD
authors.lastname: Ciccarelli
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Garcia-Perez
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D051379:Mice; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D012097:Repressor Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C497230:ST18 protein, human; C067857:MCC protein, human
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