Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

Tang, Zuojian; Steranka, Jared P.; Ma, Sisi; Grivainis, Mark; Rodić, Nemanja; Huang, Cheng Ran Lisa; Shih, Ie Ming; Wang, Tian Li; Boeke, Jef D.; Fenyö, David; Burns, Kathleen H.

doi:10.1073/pnas.1619797114

Cited by 90 publications

(118 citation statements)

References 49 publications

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“…No exonic tumor-specific mouse L1 insertions were detected. In this regard, the genomic distribution of mouse tumor-specific L1 insertions, although involving at this stage a handful of events, resembles patterns reported for human cancers, where L1 insertions found in exons of known cancer genes (Miki et al 1992;Helman et al 2014;Scott et al 2016) are far rarer than such events located in introns , including the example of the ST18 oncogene (Shukla et al 2013;Rava et al 2017) and a more recent instance in the tumor suppressor gene BRCA1 (Tang et al 2017). Although the oncogenic impact of intronic tumor-specific L1 insertions is more difficult to mechanistically assess than exonic events, they are also far more numerous and are therefore a potentially important and underexplored class of mutation encountered in mammalian cancers .…”

Section: Discussionsupporting

confidence: 52%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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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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Section: Discussionsupporting

confidence: 52%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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“…Targeted resequencing tools exploit specific sequence features of young L1s to selectively amplify and sequence novel L1 insertion junctions. These assays are similar to the previously described L1 Display [82] and L1-Seq [51] assays, often with further improvements in multiplexing, genome coverage, and enrichment of L1 junction fragments prior to sequencing [71,72,77,78,79,81,83,84]. With the decreased price of WGS, and the availability of such data in public repositories, several groups have developed bioinformatics tools to discover somatic L1 insertions in silico using WGS or WES data [70,74,75,80].…”

Section: Somatic L1 Activity In Human Genomesmentioning

confidence: 90%

The Role of Somatic L1 Retrotransposition in Human Cancers

Scott

Devine

2017

Viruses

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The human LINE-1 (or L1) element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1-encoded proteins. L1 elements remain actively mobile today and continue to mutagenize human genomes. Importantly, when new insertions disrupt gene function, they can cause diseases. Historically, L1s were thought to be active in the germline but silenced in adult somatic tissues. However, recent studies now show that L1 is active in at least some somatic tissues, including epithelial cancers. In this review, we provide an overview of these recent developments, and examine evidence that somatic L1 retrotransposition can initiate and drive tumorigenesis in humans. Recent studies have: (i) cataloged somatic L1 activity in many epithelial tumor types; (ii) identified specific full-length L1 source elements that give rise to somatic L1 insertions; and (iii) determined that L1 promoter hypomethylation likely plays an early role in the derepression of L1s in somatic tissues. A central challenge moving forward is to determine the extent to which L1 driver mutations can promote tumor initiation, evolution, and metastasis in humans.

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“…Several studies have used NGS to investigate TEs, especially those associated with humans and diseases (e.g., Ewing & Kazazian, ; Ewing & Kazazian, , Tang et al, ; Tubio et al, ). The MobiSeq method presented here can generate many thousands of unique sequences per sample, each containing the TE sequence and the flanking genomic regions, which are subsequently used for SNP discovery and genotyping.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have used NGS to investigate TEs, especially those associated with humans and diseases (e.g., Ewing & Kazazian, REY-IGLESIA ET AL. | 513 2010; Ewing & Kazazian, 2011, Tang et al, 2017Tubio et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

MobiSeq: De novo SNP discovery in model and non‐model species through sequencing the flanking region of transposable elements

Rey‐Iglesia

Gopalakrishan

Carøe

et al. 2019

Molecular Ecology Resources

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In recent years, the availability of reduced representation library (RRL) methods has catalysed an expansion of genome‐scale studies to characterize both model and non‐model organisms. Most of these methods rely on the use of restriction enzymes to obtain DNA sequences at a genome‐wide level. These approaches have been widely used to sequence thousands of markers across individuals for many organisms at a reasonable cost, revolutionizing the field of population genomics. However, there are still some limitations associated with these methods, in particular the high molecular weight DNA required as starting material, the reduced number of common loci among investigated samples, and the short length of the sequenced site‐associated DNA. Here, we present MobiSeq, a RRL protocol exploiting simple laboratory techniques, that generates genomic data based on PCR targeted enrichment of transposable elements and the sequencing of the associated flanking region. We validate its performance across 103 DNA extracts derived from three mammalian species: grey wolf (Canis lupus), red deer complex (Cervus sp.) and brown rat (Rattus norvegicus). MobiSeq enables the sequencing of hundreds of thousands loci across the genome and performs SNP discovery with relatively low rates of clonality. Given the ease and flexibility of MobiSeq protocol, the method has the potential to be implemented for marker discovery and population genomics across a wide range of organisms—enabling the exploration of diverse evolutionary and conservation questions.

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Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

Cited by 90 publications

References 49 publications

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

The Role of Somatic L1 Retrotransposition in Human Cancers

MobiSeq: De novo SNP discovery in model and non‐model species through sequencing the flanking region of transposable elements

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