Landscape of G-quadruplex DNA structural regions in breast cancer

Area of Science:

• Genomics
• Cancer Biology
• Structural Biology

Background:

• Anticancer therapy response is limited by tumor heterogeneity.
• G-quadruplex (G4) DNA structures are increasingly recognized for their role in cancer.

Purpose of the Study:

• To map G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in breast cancer patient-derived tumor xenograft (PDTX) models.
• To investigate the association of ∆G4Rs with gene expression, mutations, and breast cancer subtypes.
• To explore the therapeutic potential of targeting G4 structures.

Main Methods:

• Analysis of ∆G4R landscapes in 22 breast cancer PDTX models.
• Correlation of ∆G4R distribution with gene promoters, somatic mutations, and transcription factor programs.
• Stratification of PDTXs into G4-based subtypes and integrative clusters (ICs).
• Assessment of G4-targeting small molecule sensitivity in PDTX cultures.

Main Results:

• ∆G4Rs are linked to amplified gene promoters and somatic single-nucleotide variants.
• G4 landscapes identified seven transcription factor programs and stratified PDTXs into at least three G4-based subtypes.
• Most PDTXs exhibited multiple breast cancer subtypes (ICs), often with aggressive triple-negative IC10 gene activity.
• PDTX models with higher ∆G4R levels showed increased sensitivity to G4-targeting drugs.

Conclusions:

• G4 landscapes provide insights into intratumor heterogeneity in breast cancer PDTX models.
• G4-based stratification improves breast cancer classification and identifies potential therapeutic vulnerabilities.
• Targeting G4 DNA represents a promising strategy for novel breast cancer treatments.