L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

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...

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Bibliographic Details
Published in:	Genome research 2018-05, Vol.28 (5), p.639-653
Main Authors:	Schauer, Stephanie N, Carreira, Patricia E, Shukla, Ruchi, Gerhardt, Daniel J, Gerdes, Patricia, Sanchez-Luque, Francisco J, Nicoli, Paola, Kindlova, Michaela, Ghisletti, Serena, Santos, Alexandre Dos, Rapoud, Delphine, Samuel, Didier, Faivre, Jamila, Ewing, Adam D, Richardson, Sandra R, Faulkner, Geoffrey J
Format:	Article
Language:	eng
Subjects:	Abuse Adult Aged Aged, 80 and over Animals ATP Binding Cassette Transporter, Subfamily B - genetics ATP-Binding Cassette Sub-Family B Member 4 Biochemistry, Molecular Biology Cancer Carcinogenesis Carcinoma, Hepatocellular - genetics Cell Transformation, Neoplastic - genetics Cholangiocarcinoma Chromosome 22 Drug abuse Female Genomes Genomics Hepatitis Hepatitis B Hepatitis C Hepatocellular carcinoma Human health and pathology Humans Hépatology and Gastroenterology Insertion Life Sciences Liver - metabolism Liver - pathology Liver Neoplasms - genetics Long Interspersed Nucleotide Elements - genetics Male Mammals Mammals - genetics Mice, Knockout Middle Aged Mutagenesis Mutagenesis, Insertional Nodules Retroelements - genetics Retrotransposition Tumors
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Summary:	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 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 subfamily elements, and one G subfamily example. One of the T insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T 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.
ISSN:	1088-9051 1549-5469