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

Fingerprint

Retroelements
Hepatocellular Carcinoma
Neoplasms
Mutagenesis
Mammals
Liver
Long Interspersed Nucleotide Elements
Tissue Donors
Genome
Chromosomes, Human, Pair 22
Cholangiocarcinoma
Hepatitis B
Hepacivirus
Alcoholism
Cultured Cells
Carcinogenesis
Polymerase Chain Reaction

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

Cite this

Schauer, S. N., Carreira, P. E., Shukla, R., Gerhardt, D. J., Gerdes, P., Sanchez-Luque, F. J., ... 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

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. / 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.

In: Genome Research, Vol. 28, No. 5, 2018, p. 639-653.

Research output: Contribution to journalArticle

Schauer, SN, Carreira, PE, Shukla, R, Gerhardt, DJ, Gerdes, P, Sanchez-Luque, FJ, Nicoli, P, Kindlova, M, Ghisletti, S, Dos Santos, AD, Rapoud, D, Samuel, D, Faivre, J, Ewing, AD, Richardson, SR & Faulkner, GJ 2018, 'L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis', Genome Research, vol. 28, no. 5, pp. 639-653. https://doi.org/10.1101/gr.226993.117
Schauer SN, Carreira PE, Shukla R, Gerhardt DJ, Gerdes P, Sanchez-Luque FJ et al. L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Research. 2018;28(5):639-653. https://doi.org/10.1101/gr.226993.117
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. / L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. In: Genome Research. 2018 ; Vol. 28, No. 5. pp. 639-653.
@article{fb4066673d2840f2a86812c6d5d08cdd,
title = "L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis",
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. {\circledC} 2018 Schauer et al.",
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",
author = "S.N. Schauer and P.E. Carreira and R. Shukla and D.J. Gerhardt and P. Gerdes and F.J. Sanchez-Luque and P. Nicoli and M. Kindlova and S. Ghisletti and {Dos Santos}, A.D. and D. Rapoud and D. Samuel and J. Faivre and A.D. Ewing and S.R. Richardson and G.J. Faulkner",
note = "Cited By :5 Export Date: 5 February 2019 CODEN: GEREF Correspondence Address: Ewing, A.D.; Mater Research Institute, University of QueenslandAustralia; email: adam.ewing@mater.uq.edu.au Chemicals/CAS: ABC transporter subfamily B, 149200-37-3, 208997-77-7; ATP Binding Cassette Transporter, Sub-Family B; P-glycoprotein 2; Retroelements Funding details: FP7 Ideas: European Research Council, IDEAS-ERC, 259743 Funding details: Universit{\'e} Paris-Sud Funding details: National Health and Medical Research Council, NHMRC Funding details: Australian Research Council, ARC, DE150101117 Funding details: National Health and Medical Research Council, NHMRC, GNT1045991 Funding details: National Health and Medical Research Council, NHMRC, GNT1067983 Funding details: National Health and Medical Research Council, NHMRC, GNT1068789 Funding details: National Health and Medical Research Council, NHMRC, GNT1042449 Funding details: National Health and Medical Research Council, NHMRC, GNT1106206 Funding text 1: Pr. Denis Castaing, Pr. Antonio Sa Cunha, and Pr. Eric Vibert, who are surgeons in the Centre H{\'e}patobiliaire, Villejuif, and the Tissue Biobank Group (AP-HP and Universit{\'e} Paris-Sud) for providing human specimens. We thank members of the Faulkner laboratory for helpful advice and discussion. This study was supported by CSL Centenary Fellowship and National Health and Medical Research Council (NHMRC) Project Grant (GNT1042449, GNT1045991, GNT1067983, GNT1068789, and GNT1106206) funding to G.J.F., the EU FP7 under grant agreement No. 259743 underpinning the MODHEP consortium to J.F., D.S., and G.J.F., and an Australian Research Council Discovery Early Career Researcher Award (DE150101117) to A.D.E. 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year = "2018",
doi = "10.1101/gr.226993.117",
language = "English",
volume = "28",
pages = "639--653",
journal = "Genome Research",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "5",

}

TY - JOUR

T1 - L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

AU - Schauer, S.N.

AU - Carreira, P.E.

AU - Shukla, R.

AU - Gerhardt, D.J.

AU - Gerdes, P.

AU - Sanchez-Luque, F.J.

AU - Nicoli, P.

AU - Kindlova, M.

AU - Ghisletti, S.

AU - Dos Santos, A.D.

AU - Rapoud, D.

AU - Samuel, D.

AU - Faivre, J.

AU - Ewing, A.D.

AU - Richardson, S.R.

AU - Faulkner, G.J.

N1 - Cited By :5 Export Date: 5 February 2019 CODEN: GEREF Correspondence Address: Ewing, A.D.; Mater Research Institute, University of QueenslandAustralia; email: adam.ewing@mater.uq.edu.au Chemicals/CAS: ABC transporter subfamily B, 149200-37-3, 208997-77-7; ATP Binding Cassette Transporter, Sub-Family B; P-glycoprotein 2; Retroelements Funding details: FP7 Ideas: European Research Council, IDEAS-ERC, 259743 Funding details: Université Paris-Sud Funding details: National Health and Medical Research Council, NHMRC Funding details: Australian Research Council, ARC, DE150101117 Funding details: National Health and Medical Research Council, NHMRC, GNT1045991 Funding details: National Health and Medical Research Council, NHMRC, GNT1067983 Funding details: National Health and Medical Research Council, NHMRC, GNT1068789 Funding details: National Health and Medical Research Council, NHMRC, GNT1042449 Funding details: National Health and Medical Research Council, NHMRC, GNT1106206 Funding text 1: Pr. Denis Castaing, Pr. Antonio Sa Cunha, and Pr. Eric Vibert, who are surgeons in the Centre Hépatobiliaire, Villejuif, and the Tissue Biobank Group (AP-HP and Université Paris-Sud) for providing human specimens. We thank members of the Faulkner laboratory for helpful advice and discussion. This study was supported by CSL Centenary Fellowship and National Health and Medical Research Council (NHMRC) Project Grant (GNT1042449, GNT1045991, GNT1067983, GNT1068789, and GNT1106206) funding to G.J.F., the EU FP7 under grant agreement No. 259743 underpinning the MODHEP consortium to J.F., D.S., and G.J.F., and an Australian Research Council Discovery Early Career Researcher Award (DE150101117) to A.D.E. 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PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - 3' untranslated region

KW - alcohol abuse

KW - animal experiment

KW - animal model

KW - Article

KW - bile duct carcinoma

KW - chromosome 22

KW - clinical article

KW - controlled study

KW - epigenetics

KW - gene insertion

KW - genomics

KW - Hepatitis B virus

KW - Hepatitis C virus

KW - human

KW - human tissue

KW - liver carcinogenesis

KW - liver cell carcinoma

KW - long interspersed repeat

KW - mammal

KW - mouse

KW - nonhuman

KW - polymerase chain reaction

KW - priority journal

KW - retroposon

KW - whole genome sequencing

KW - adult

KW - aged

KW - animal

KW - cell transformation

KW - female

KW - gene expression regulation

KW - genetics

KW - knockout mouse

KW - liver

KW - liver tumor

KW - male

KW - metabolism

KW - middle aged

KW - pathology

KW - very elderly

KW - ABC transporter subfamily B

KW - P-glycoprotein 2

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - ATP Binding Cassette Transporter, Sub-Family B

KW - Carcinoma, Hepatocellular

KW - Cell Transformation, Neoplastic

KW - Female

KW - Humans

KW - Liver

KW - Liver Neoplasms

KW - Long Interspersed Nucleotide Elements

KW - Male

KW - Mammals

KW - Mice, Knockout

KW - Middle Aged

KW - Mutagenesis, Insertional

KW - Retroelements

U2 - 10.1101/gr.226993.117

DO - 10.1101/gr.226993.117

M3 - Article

VL - 28

SP - 639

EP - 653

JO - Genome Research

JF - Genome Research

SN - 1088-9051

IS - 5

ER -