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L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis.

Lookup NU author(s): Dr Ruchi ShuklaORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

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 T_F subfamily elements, and one G_F subfamily example. One of the T_F insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T_F 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.

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Author(s): Schauer SN, Carreira PE, Shukla R, Gerhardt DJ, Gerdes P, Sanchez-Luque FJ, Nicoli P, Kindlova M, Ghisletti S, Santos AD, Rapoud D, Samuel D, Faivre J, Ewing AD, Richardson SR, Faulkner GJ

Publication type: Article

Publication status: Published

Journal: Genome Research

Year: 2018

Volume: 28

Issue: 5

Pages: 639-653

Online publication date: 11/04/2018

Acceptance date: 26/03/2018

Date deposited: 03/05/2018

ISSN (print): 1088-9051

ISSN (electronic): 1549-5469

Publisher: CSH Press

URL: https://doi.org/10.1101/gr.226993.117

DOI: 10.1101/gr.226993.117

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