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. Overall design: Examination of 22 different PDTX breast cancer models by quantitative G4-ChIP-seq.