L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

Stephanie N Schauer, Patricia E Carreira, Ruchi Shukla, Daniel J Gerhardt, Patricia Gerdes, Francisco J Sanchez-Luque, Paola Nicoli, Michaela Kindlova, Serena Ghisletti, Alexandre Dos Santos, Delphine Rapoud, Didier Samuel, Jamila Faivre, Adam D Ewing, Sandra R Richardson, Geoffrey J Faulkner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)639-653
Number of pages15
JournalGenome Research
Volume28
Issue number5
DOIs
Publication statusPublished - May 2018

Keywords

  • ATP Binding Cassette Transporter, Subfamily B/genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Carcinoma, Hepatocellular/genetics
  • Cell Transformation, Neoplastic/genetics
  • Female
  • Humans
  • Liver/metabolism
  • Liver Neoplasms/genetics
  • Long Interspersed Nucleotide Elements/genetics
  • Male
  • Mammals/genetics
  • Mice, Knockout
  • Middle Aged
  • Mutagenesis, Insertional
  • Retroelements/genetics

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