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Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic r...

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Detalles Bibliográficos
Autores principales: Jung, Hyunchul, Choi, Jung Kyoon, Lee, Eunjung Alice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071633/
https://www.ncbi.nlm.nih.gov/pubmed/29970450
http://dx.doi.org/10.1101/gr.231837.117
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author Jung, Hyunchul
Choi, Jung Kyoon
Lee, Eunjung Alice
author_facet Jung, Hyunchul
Choi, Jung Kyoon
Lee, Eunjung Alice
author_sort Jung, Hyunchul
collection PubMed
description Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole-genome and matched RNA-sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense-mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein–Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers.
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spelling pubmed-60716332018-08-14 Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers Jung, Hyunchul Choi, Jung Kyoon Lee, Eunjung Alice Genome Res Research Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole-genome and matched RNA-sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense-mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein–Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers. Cold Spring Harbor Laboratory Press 2018-08 /pmc/articles/PMC6071633/ /pubmed/29970450 http://dx.doi.org/10.1101/gr.231837.117 Text en © 2018 Jung et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Jung, Hyunchul
Choi, Jung Kyoon
Lee, Eunjung Alice
Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title_full Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title_fullStr Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title_full_unstemmed Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title_short Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers
title_sort immune signatures correlate with l1 retrotransposition in gastrointestinal cancers
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071633/
https://www.ncbi.nlm.nih.gov/pubmed/29970450
http://dx.doi.org/10.1101/gr.231837.117
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