L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

S.N. Schauer, P.E. Carreira, R. Shukla, D.J. Gerhardt, P. Gerdes, F.J. Sanchez-Luque, P. Nicoli, M. Kindlova, S. Ghisletti, A.D. Dos Santos, D. Rapoud, D. Samuel, J. Faivre, A.D. Ewing, S.R. Richardson, G.J. Faulkner

Research output: Contribution to journalArticle

Abstract

The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors. © 2018 Schauer et al.
Original languageEnglish
Pages (from-to)639-653
Number of pages15
JournalGenome Research
Volume28
Issue number5
DOIs
Publication statusPublished - 2018

Keywords

  • 3' untranslated region
  • alcohol abuse
  • animal experiment
  • animal model
  • Article
  • bile duct carcinoma
  • chromosome 22
  • clinical article
  • controlled study
  • epigenetics
  • gene insertion
  • genomics
  • Hepatitis B virus
  • Hepatitis C virus
  • human
  • human tissue
  • liver carcinogenesis
  • liver cell carcinoma
  • long interspersed repeat
  • mammal
  • mouse
  • nonhuman
  • polymerase chain reaction
  • priority journal
  • retroposon
  • whole genome sequencing
  • adult
  • aged
  • animal
  • cell transformation
  • female
  • gene expression regulation
  • genetics
  • knockout mouse
  • liver
  • liver tumor
  • male
  • metabolism
  • middle aged
  • pathology
  • very elderly
  • ABC transporter subfamily B
  • P-glycoprotein 2
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • ATP Binding Cassette Transporter, Sub-Family B
  • Carcinoma, Hepatocellular
  • Cell Transformation, Neoplastic
  • Female
  • Humans
  • Liver
  • Liver Neoplasms
  • Long Interspersed Nucleotide Elements
  • Male
  • Mammals
  • Mice, Knockout
  • Middle Aged
  • Mutagenesis, Insertional
  • Retroelements

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  • Cite this

    Schauer, S. N., Carreira, P. E., Shukla, R., Gerhardt, D. J., Gerdes, P., Sanchez-Luque, F. J., Nicoli, P., Kindlova, M., Ghisletti, S., Dos Santos, A. D., Rapoud, D., Samuel, D., Faivre, J., Ewing, A. D., Richardson, S. R., & Faulkner, G. J. (2018). L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Research, 28(5), 639-653. https://doi.org/10.1101/gr.226993.117