Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma

Rodić, Nemanja; Steranka, Jared P.; Makohon-Moore, Alvin; Moyer, Allison; Shen, Peilin; Sharma, Reema; Kohutek, Zachary A.; Huang, Cheng Ran Lisa; Ahn, Daniel H.; Mita, Paolo; Taylor, Martin S.; Barker, Norman; Hruban, Ralph H.; Iacobuzio‐Donahue, Christine A.; Boeke, Jef D.; Burns, Kathleen H.

doi:10.1038/nm.3919

Cited by 130 publications

(133 citation statements)

References 29 publications

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“…The five parameters are used for the training set model are as follows: a) Width: the width of the enriched target region (log 2 -based value) b) Depth: the average coverage enriched target region (log 2 -based value) c) Variant index: alignment mismatches and indels within the peak interval (sum of the number of mismatches and indels divided by the sum of the number of base pairs and the number of reads) d) pA tail purity of each consensus sequence at the predicted 3′ end of the insertion site within a segment of specified length (%) e) Number of J supporting the predicted site We previously described a study of somatic retrotransposition of LINE-1 in patients with lethal metastatic pancreatic ductal adenocarcinoma (PDAC) (27), in which we used TIPseq to map LINE-1 insertions in a series of primary and metastatic lesions, as well as matched normal genomic DNA (germ line) from the same individuals. Here, we applied TIPseqHunter to analyze data from 36 of these TIPseq experiments.…”

Section: Resultsmentioning

confidence: 99%

“…Information on these somatic insertions is available on the TranspoScope web site. We are able to detect 76 of the 80 previously reported, PCR-validated L1 insertions (27) using TIPseqHunter, giving a sensitivity of 95%. Of 20 additional candidates identified by TIPseqHunter, we tested four high-quality insertions and successfully PCR-validated all four of these insertions.…”

Section: Identification Of Tumor-specific Insertion Sites and Pcr Valmentioning

confidence: 86%

“…Recently, however, strategies for mapping these elements have been developed based on selective PCR amplification (15)(16)(17), hybridizationbased enrichment (18,19), and read selection from wholegenome sequencing data (20)(21)(22). These studies underscore the continued activity of LINE-1 in modern humans, and demonstrated somatic insertions in several types of human malignancy (15,19,(22)(23)(24)(25)(26)(27).…”

Section: Significancementioning

confidence: 99%

“…Here, we describe a strategy for selectively amplifying genomic DNA 3′ of insertions of active subfamilies of human LINE-1 for Illumina sequencing (17,27,28). We also describe informatics pipeline, machine-learning-based computational pipeline transposon insertion profiling by next-generation sequencing (TIPseq) Hunter (TIPseqHunter; https://github.com/fenyolab/ TIPseqHunter, with supporting files available at openslice.…”

Section: Significancementioning

confidence: 99%

“…As previously reported (27), PDAC samples were acquired through a rapid autopsy protocol; we had available matched normal primary tumor and metastatic tumor samples from 10 individuals, and matched normal and primary tumor samples from three individuals. Using TIPseqHunter, we identified 88 so-called "progenitor L1" insertions, somatically acquired LINE-1 insertions shared by a primary tumor and a metastatic site of disease in the case, and not found in normal genomic DNA (gDNA) from the same patient.…”

Section: Identification Of Tumor-specific Insertion Sites and Pcr Valmentioning

confidence: 99%

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

Tang

Steranka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian genomes are replete with interspersed repeats reflecting the activity of transposable elements. These mobile DNAs are self-propagating, and their continued transposition is a source of both heritable structural variation as well as somatic mutation in human genomes. Tailored approaches to map these sequences are useful to identify insertion alleles. Here, we describe in detail a strategy to amplify and sequence long interspersed element-1 (LINE-1, L1) retrotransposon insertions selectively in the human genome, transposon insertion profiling by next-generation sequencing (TIPseq). We also report the development of a machine-learning-based computational pipeline, TIPseqHunter, to identify insertion sites with high precision and reliability. We demonstrate the utility of this approach to detect somatic retrotransposition events in highgrade ovarian serous carcinoma.retrotransposon | TIPseq | human | LINE-1 | ovarian cancer

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Section: Resultsmentioning

confidence: 99%

Section: Identification Of Tumor-specific Insertion Sites and Pcr Valmentioning

confidence: 86%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Identification Of Tumor-specific Insertion Sites and Pcr Valmentioning

confidence: 99%

See 3 more Smart Citations

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

Tang

Steranka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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111

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Repetitive Elements and Human Disorders

Morales

Deininger

2017

Encyclopedia of Life Sciences

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Repetitive sequences, consisting largely of transposable elements (TEs), comprise almost two‐thirds of the human genome. Non‐long‐terminal repeat (non‐LTR) TEs such as L1s, Alus and SVAs are still actively multiplying. Ongoing proliferation of these non‐LTR TEs results in a significant level of disease‐causing mutations through insertional mutagenesis, non‐allelic recombination (NAR) and the induction of genomic instability. NAR between Alu elements represents a major form of genetic instability leading to deletions, duplications and complex rearrangements. Between these different mechanisms, TEs have not only contributed a great deal to the evolution of the genome but also continue to generate germline mutations that cause a variety of diseases and potentially the progression of somatic diseases like cancer. With the advent of sequencing technologies, the future holds the promise of uncovering this role. Key Concepts Transposable elements (TEs) are DNA segments that are able to create new copies within the genome. These TEs are known to cause a variety of germline diseases through insertional mutagenesis and mutagenic recombination. TEs provide opportunities for non‐allelic recombination events to cause DNA rearrangements. There is a sharp increase in TE insertions in most epithelial cancers as well as increased opportunities for non‐allelic recombination. The overall impact of these TEs in a number of somatic diseases, particularly epithelial cancers, is under investigation. High‐throughput sequencing approaches are being utilised to better understand mobile element biology.

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Recently Mobilised Transposons in the Human Genome

Saha

2019

Encyclopedia of Life Sciences

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Transposable elements make up approximately half of the human genome. Apart from an evolutionary role in altering the genomic landscape and gene expression, recent discoveries have brought into focus the scale and impact of active movement by non‐LTR retrotransposons, both in the germline and in somatic niches. Heritable insertions that originate from either early embryonic or germ cell development have contributed to over 100 cases of human genetic diseases. Alu, L1 and SVA contribute to 60%, 25% and 10% of disease‐causing germline insertions, respectively. In contrast, L1 retrotransposition is responsible for the majority of nonheritable (or somatic) insertions found in the brain and many types of cancers. A multidisciplinary effort is required to fully understand the role of active retrotransposition in human physiology and pathophysiology. Key Concepts Recently mobilised transposons in the human genome are confined to three types of non‐LTR retrotransposons: L1, Alu and SVA. Ongoing retrotransposition in the germline has contributed to over 100 cases of tumour and nontumour human genetic diseases, including 21 cases of neurofibromatosis type 1 (NF1). Early embryonic development is a critical window for retrotransposition and may harbour excessive insertional activities. Elevated L1 retrotransposition in germ cells is expected in individuals with partially compromised piRNA pathway. Human brain is a hub for somatic retrotransposition during neuronal development. Its implication on neuronal function or dysfunction (friend or foe) remains to be elucidated. Human cancers can be categorised into very‐high, high, medium, low and very‐low insertional activity groups. Some insertions are cancer drivers but the majority are likely passenger events.

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Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma

Cited by 130 publications

References 29 publications

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

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

Repetitive Elements and Human Disorders

Recently Mobilised Transposons in the Human Genome

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