Landscape of G-quadruplex DNA structural regions in breast cancer

Response and resistance to anticancer therapies vary due to inter- and intra-tumour heterogeneity. Here, we developed and applied a quantitative chromatin immunoprecipitation sequencing methodology to map differentially enriched G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in 22 breast cancer patient-derived tumour xenograft (PDTX) models. ∆G4Rs are significantly more associated with the promoter of highly amplified and expressed genes, and with somatic single-nucleotide variant mutations. Specific ∆G4Rs associate with certain patterns of breast cancer TF occupancy, revealing 7 distinct transcription factor programs with differential activities across PDTXs. Collectively, ∆G4Rs report on the genomic, transcriptomic and regulatory architecture of breast cancer. ∆G4R abundance and locations stratify PDTXs into at least three G4-based subtypes. ∆G4Rs of the majority of PDTXs (14/22) associated with more than one distinct breast cancer subtype, which we also call an integrative cluster (IC). This suggests the frequent coexistence of multiple breast cancer states within a PDTX model; the majority, in contrast to expectation, displaying aggressive triple-negative IC10. Short-term cultures of PDTX models with increased ∆G4R levels are more sensitive to small molecules targeting G4 DNA. Thus, G4 DNA structural landscapes revealed additional IC-related intra-tumour heterogeneity in PDTX biopsies, improving their cancer stratification and potentially new treatment strategies. Examination of 22 different PDTX breast cancer models by quantitative G4-ChIP-seq.