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 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.

LINE-1 retrotransposition impacts the genome of human pre-implantation embryos and extraembryonic tissues

“…As a consequence, retrotransposition is ongoing in the current human population, and new heritable LINE-1 insertions can sporadically cause genetic disease (Hancks and Kazazian, 2016;Kazazian et al, 1988). are also active in some somatic tissues, such as the brain (Baillie et al, 2011;Coufal et al, 2011;Evrony et al, 2012;Macia et al, 2017;Muotri et al, 2005;Upton et al, 2015) or epithelial tumors (Doucet-O'Hare et al, 2016;Ewing et al, 2015;Helman et al, 2014;Iskow et al, 2010;Lee et al, 2012;Miki et al, 1992;Rodic et al, 2015;Schauer et al, 2018;Scott et al, 2016;Shukla et al, 2013;Solyom et al, 2012;Tang et al, 2017;Tubio et al, 2014), recently reviewed in (Carreira et al, 2013;Scott and Devine, 2017)). In contrast, retrotransposition in other somatic tissues may be uncommon (Garcia-Perez et al, 2016;Macia et al, 2017).…”

Host–transposon interactions: conflict, cooperation, and cooption

“…The repetitive nature of TE families provides a substrate for ectopic recombination events that can lead to chromosomal rearrangements, often with deleterious consequences (Montgomery et al 1991;Ade et al 2013;Bennetzen and Wang 2014;Hancks and Kazazian 2016). TE-encoded products (RNA, cDNA, and proteins), even with compromised functionalities, can be toxic, and their accumulation to aberrant amounts are associated with and increasingly recognized as directly contributing to various disease states, including cancer, senescence, and chronic inflammation (Lee et al 2012a;Tubio et al 2014;Burns 2017;Tang et al 2017;Bourque et al 2018;Dubnau 2018;Schauer et al 2018;De Cecco et al 2019).…”

Heritable L1 Retrotransposition Events During Development: Understanding Their Origins

“…All 11 insertions belonged to the L1 T F subfamily, which is consistent with reports of spontaneous disease‐causing L1 insertions in mice, although examination of de novo retrotransposition events in different inbred mouse strains may reveal strain‐specific activity of G F and A subfamily elements. Indeed, we have very recently uncovered a tumor‐specific L1 G F insertion in a mouse model of hepatocellular carcinoma on a congenic FVB.129 Sv background …”

“…In adult testis, ORF1p is expressed in round and elongating spermatids, and can be faintly and rarely detected in spermatocytes . L1 ORF1p can also be detected in fetal male and female germ cells from embryonic day 15.5 …”