Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity¹. 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.

由于肿瘤间和肿瘤内的异质性，抗癌治疗的反应和耐药性有所不同¹ 。在这里，我们在 22 个乳腺癌患者来源的肿瘤异种移植 (PDTX) 模型中绘制了差异富集的 G 四链体 (G4) DNA 结构形成区域 (ΔG4R)。 ΔG4R 与显示高表达的高度扩增基因的启动子以及体细胞单核苷酸变异相关。 ΔG4R 景观的差异揭示了 PDTX 中的七个转录因子程序。 ΔG4R 丰度和位置将 PDTX 分为至少三个基于 G4 的亚型。大多数 PDTX 中的 ΔG4R（22 个中的 14 个）被发现与不止一种乳腺癌亚型相关，我们也将其称为整合簇 (IC) ² 。这表明 PDTX 模型中多种乳腺癌状态频繁共存，其中大多数表现出侵袭性三阴性 IC10 基因活性。 ΔG4R 水平增加的 PDTX 模型的短期培养物对靶向 G4 DNA 的小分子更加敏感。因此，G4 景观揭示了 PDTX 活检中与 IC 相关的额外肿瘤内异质性，改善了乳腺癌分层并有可能确定新的治疗策略。