L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis (original) (raw)

  1. Patricia E. Carreira1,12,
  2. Ruchi Shukla2,12,
  3. Daniel J. Gerhardt1,3,
  4. Patricia Gerdes1,
  5. Francisco J. Sanchez-Luque1,4,
  6. Paola Nicoli5,
  7. Michaela Kindlova1,
  8. Serena Ghisletti6,
  9. Alexandre Dos Santos7,8,
  10. Delphine Rapoud7,8,
  11. Didier Samuel7,8,
  12. Jamila Faivre7,8,9,
  13. Adam D. Ewing1,
  14. Sandra R. Richardson1 and
  15. Geoffrey J. Faulkner1,10,11
  16. 1Mater Research Institute–University of Queensland, Woolloongabba, QLD 4102, Australia;
  17. 2Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom;
  18. 3Invenra, Incorporated, Madison, Wisconsin 53719, USA;
  19. 4Department of Genomic Medicine, GENYO, Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government, PTS Granada, 18016 Granada, Spain;
  20. 5Department of Experimental Oncology, European Institute of Oncology, 20146 Milan, Italy;
  21. 6Humanitas Clinical and Research Center, 20089 Milan, Italy;
  22. 7INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France;
  23. 8Université Paris-Sud, Faculté de Médecine, Villejuif 94800, France;
  24. 9Assistance Publique-Hôpitaux de Paris (AP-HP), Pôle de Biologie Médicale, Paul-Brousse University Hospital, Villejuif 94800, France;
  25. 10School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia;
  26. 11Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia
  27. ↵12 These authors contributed equally to this work.

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.

Footnotes

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.