A team of researchers from the University of Cambridge have unravelled the complex landscape of G-quadruplexes and revealed their role within certain subtypes of breast cancer heterogeneity.
G-quadruplexes (G4s) are four-stranded secondary structures that form in certain G-rich DNA regions of the genome when a single strand of DNA loops out and doubles back on itself to form a stack of guanine tetrads.
The team, led by Professor Shankar Balasubramanian, previously identified that G4s could form within the human genome. They also developed techniques to profile these regions in both DNA and chromatin, where they revealed prominent formation of G4s within promoters of highly expressed cancer genes. Computational predictions have linked these structures to genomic instability and highlighted their role during DNA replication and transcription.
In this new study published in Nature Genetics, the team used their quantitative G4-ChIP-seq methodology to map these structures within 22 breast cancer patient-derived tumour xenograft (PDTX) models. These PDTX models were derived by taking biopsies from patients and then transplanting and growing the tumours in mice.
Dr Robert Hänsel-Hertsch, first author on the publication, stated:
“The abundance and location of G-quadruplexes in these biopsies gives us a clue to their importance in cancer biology and to the heterogeneity of these breast cancers.”
He added, “Importantly, it highlights another potential weak spot that we might use against the breast tumour to develop better treatments for our patients.”
The team found that differentially enriched G4 regions were associated with promoters of highly amplified genes. They also found that in most PDTX models (14 of 22) these differentially enriched regions were associated with more than one breast cancer subtype, which they referred to as an integrative cluster. This suggests the frequent coexistence within a PDTX model of multiple breast cancer states. Understanding the G4 landscape, combined with established knowledge of subtypes, could help refine the genomic, transcriptomic and regulatory classification of breast cancer.
The team also discovered that short-term cultures of PDTX models with increased differentially enriched G4 regions were more sensitive to small molecules targeting G4 DNA. This demonstrates the potential of G4s as genomic features that could be used for future diagnostics and therapeutics.