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G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers

G-quadruplexes (G4) are noncanonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SV) in cancers could provide a better understanding of the role of G4 formation in cancer developmen...

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Autores principales: Zhang, Rongxin, Shu, Huiling, Wang, Yuqi, Tao, Tiantong, Tu, Jing, Wang, Cheng, Mergny, Jean-Louis, Sun, Xiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102852/
https://www.ncbi.nlm.nih.gov/pubmed/36791413
http://dx.doi.org/10.1158/0008-5472.CAN-22-3089
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author Zhang, Rongxin
Shu, Huiling
Wang, Yuqi
Tao, Tiantong
Tu, Jing
Wang, Cheng
Mergny, Jean-Louis
Sun, Xiao
author_facet Zhang, Rongxin
Shu, Huiling
Wang, Yuqi
Tao, Tiantong
Tu, Jing
Wang, Cheng
Mergny, Jean-Louis
Sun, Xiao
author_sort Zhang, Rongxin
collection PubMed
description G-quadruplexes (G4) are noncanonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SV) in cancers could provide a better understanding of the role of G4 formation in cancer development and progression. In this study, we combined bioinformatic approaches and multiomics data to investigate the connection between G4s and the somatic SVs. Somatic SV breakpoints were significantly enriched in G4 regions, regardless of SV subtypes. This enrichment was only observed in regions demonstrated to form G4s in cells (“active quadruplexes”), rather than in regions with a sequence compatible with G4 formation but without confirmed G4 formation (“potential quadruplexes”). Several genomic features affected the connection between G4s and SVs, with the enrichment being notably strengthened at the boundary of topologically associated domains. Somatic breakpoints were also preferentially associated with G4 regions with earlier replication timing and open chromatin status. In patients with cancer with homologous recombination repair defects, G4s and somatic breakpoints were substantially more strongly associated. Machine learning models were constructed that showed that G4 propensity is a potent feature for predicting the density of SV breakpoints. Altogether, these findings suggest that the G4 structures play a critical role in modulating the production of somatic SVs in cancers. SIGNIFICANCE: G-quadruplex structure formation constitutes a critical step in the production of somatic structural variants in cancers, suggesting G-quadruplex structures as potential targets for future cancer prevention and treatment strategies.
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spelling pubmed-101028522023-04-15 G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers Zhang, Rongxin Shu, Huiling Wang, Yuqi Tao, Tiantong Tu, Jing Wang, Cheng Mergny, Jean-Louis Sun, Xiao Cancer Res Genome and Epigenome G-quadruplexes (G4) are noncanonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SV) in cancers could provide a better understanding of the role of G4 formation in cancer development and progression. In this study, we combined bioinformatic approaches and multiomics data to investigate the connection between G4s and the somatic SVs. Somatic SV breakpoints were significantly enriched in G4 regions, regardless of SV subtypes. This enrichment was only observed in regions demonstrated to form G4s in cells (“active quadruplexes”), rather than in regions with a sequence compatible with G4 formation but without confirmed G4 formation (“potential quadruplexes”). Several genomic features affected the connection between G4s and SVs, with the enrichment being notably strengthened at the boundary of topologically associated domains. Somatic breakpoints were also preferentially associated with G4 regions with earlier replication timing and open chromatin status. In patients with cancer with homologous recombination repair defects, G4s and somatic breakpoints were substantially more strongly associated. Machine learning models were constructed that showed that G4 propensity is a potent feature for predicting the density of SV breakpoints. Altogether, these findings suggest that the G4 structures play a critical role in modulating the production of somatic SVs in cancers. SIGNIFICANCE: G-quadruplex structure formation constitutes a critical step in the production of somatic structural variants in cancers, suggesting G-quadruplex structures as potential targets for future cancer prevention and treatment strategies. American Association for Cancer Research 2023-04-14 2023-02-15 /pmc/articles/PMC10102852/ /pubmed/36791413 http://dx.doi.org/10.1158/0008-5472.CAN-22-3089 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Genome and Epigenome
Zhang, Rongxin
Shu, Huiling
Wang, Yuqi
Tao, Tiantong
Tu, Jing
Wang, Cheng
Mergny, Jean-Louis
Sun, Xiao
G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title_full G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title_fullStr G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title_full_unstemmed G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title_short G-Quadruplex Structures Are Key Modulators of Somatic Structural Variants in Cancers
title_sort g-quadruplex structures are key modulators of somatic structural variants in cancers
topic Genome and Epigenome
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102852/
https://www.ncbi.nlm.nih.gov/pubmed/36791413
http://dx.doi.org/10.1158/0008-5472.CAN-22-3089
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