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Landscape of G-quadruplex DNA structural regions in breast cancer
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Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity 1. Here, we map differentially enriched G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in 22 breast cancer patient-derived tumor xenograft (PDTX) models. ∆G4Rs are associated with the promoters of highly amplified genes showing high expression, and with somatic single-nucleotide variants. Differences in ΔG4R landscapes reveal seven transcription factor programs across PDTXs. ∆G4R abundance and locations stratify PDTXs into at least three G4-based subtypes. ∆G4Rs in most PDTXs (14 of 22) were found to associate with more than one breast cancer subtype, which we also call an integrative cluster (IC)2. This suggests the frequent coexistence of multiple breast cancer states within a PDTX model, the majority of which display aggressive triple-negative IC10 gene activity. Short-term cultures of PDTX models with increased ∆G4R levels are more sensitive to small molecules targeting G4 DNA. Thus, G4 landscapes reveal additional IC-related intratumor heterogeneity in PDTX biopsies, improving breast cancer stratification and potentially identifying new treatment strategies.
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“as a recent study revealed G4-associated intratumor heterogeneity in breast cancer patient-derived tumor xenografts beyond current classifications (90).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [90]
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Lahnsteiner, A., Craig, S. J. C., Kamali, K., Weissensteiner, B., McGrath, B., Risch, A., & Makova, K. D. (2023) · bioRxiv · doi:10.1101/2023.11.28.569002 · Cited by 12
Nucleic Acids and Electrical Signals
McCaig, C. (2025) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/978-3-031-68827-0_12
Ultrafast light-switch properties of a G-quadruplex binder: [Ru(phen) 2 (tpphz-DC3)] 4+
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HTLV-1 antisense transcription is promoted by increased SP1 binding at 3’-LTR G-QuadruplexesPreprint
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Additional file 7 of G-quadruplexes are transcription factor binding hubs in human chromatin
Spiegel, J., Cuesta, S. M., Adhikari, S., Hänsel‐Hertsch, R., Tannahill, D., & Balasubramanian, S. (2021) · Figshare · doi:10.6084/m9.figshare.14478437
Self-citationFlynn, S. M., Dhir, S., Herka, K., Doyle, C., Melidis, L., Simeone, A., Hui, W. W. I., Tavares, R. D. C. A., Schoenfelder, S., Tannahill, D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26945571
Self-citationShen, J., Varshney, D., Simeone, A., Zhang, X., Adhikari, S., Tannahill, D., & Balasubramanian, S. (2021) · Figshare · doi:10.6084/m9.figshare.14559010
Self-citationFlynn, S. M., Dhir, S., Herka, K., Doyle, C., Melidis, L., Simeone, A., Hui, W. W. I., Tavares, R. D. C. A., Schoenfelder, S., Tannahill, D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26945553
Self-citationFlynn, S. M., Dhir, S., Herka, K., Doyle, C., Melidis, L., Simeone, A., Hui, W. W. I., Tavares, R. D. C. A., Schoenfelder, S., Tannahill, D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26945559
Self-citationAdditional file 9 of G-quadruplexes are transcription factor binding hubs in human chromatin
Spiegel, J., Cuesta, S. M., Adhikari, S., Hänsel‐Hertsch, R., Tannahill, D., & Balasubramanian, S. (2021) · Figshare · doi:10.6084/m9.figshare.14478443
Self-citation
Metadata
- Authors
- Hänsel-Hertsch, R., Simeone, A., Shea, A., Hui, W. W. I., Zyner, K. G., Marsico, G., Rueda, O. M., Bruna, A., Martin, A., Zhang, X., Adhikari, S., Tannahill, D., Caldas, C., & Balasubramanian, S.
- Affiliations
- University of Cambridge (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Balasubramanian, Shankar
- ORCID
- Venue
- Nature Genetics
- Published
- 2020-08-03
- Volume
- 52
- Issue
- 9
- Pages
- 878-883
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W3047068833
- Cited by
- 223
- References
- 37
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 42 · 2023: 39 · 2022: 27 · 2021: 48 · 2020: 8
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Cancer Research UK (C9681/A18618, C9681/A29214, C14303/A17197)
- Wellcome Trust (209441/z/17/z)
- University of Cologne | Center for Molecular Medicine Cologne, University of Cologne (2635020301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- G-quadruplex, breast cancer, patient-derived xenografts, intratumoral heterogeneity, triple-negative breast cancer, gene amplification, somatic single nucleotide variants, tumor stratification, drug sensitivity
- MeSH terms
- Breast Neoplasms, DNA, Female, Gene Expression Regulation, Humans, Promoter Regions, Genetic, Transcription Factors, G-Quadruplexes
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