Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Wuerzburg, Wuerzburg 97080, Germany.
Nucleic Acids Res. 2024 Mar 21;52(5):2198-2211. doi: 10.1093/nar/gkae098.
G-quadruplex (G4s) DNA structures have been implicated in inducing genomic instability and contributing to cancer development. However, the relationship between G4s and cancer-related single nucleotide variants (cSNVs) in clinical settings remains unclear. In this large-scale study, we integrated experimentally validated G4s with genomic cSNVs from 13480 cancer patients to investigate the spatial association of G4s with the cellular cSNV landscape. Our findings demonstrate an increase in local genomic instability with increasing local G4 content in cancer patients, suggesting a potential role for G4s in driving cSNVs. Notably, we observed distinct spatial patterns of cSNVs and common single nucleotide variants (dbSNVs) in relation to G4s, implying different mechanisms for their generation and accumulation. We further demonstrate large, cancer-specific differences in the relationship of G4s and cSNVs, which could have important implications for a new class of G4-stabilizing cancer therapeutics. Moreover, we show that high G4-content can serve as a prognostic marker for local cSNV density and patient survival rates. Our findings underscore the importance of considering G4s in cancer research and highlight the need for further investigation into the underlying molecular mechanisms of G4-mediated genomic instability, especially in the context of cancer.
G-四链体 (G4s) DNA 结构已被牵连到诱导基因组不稳定性并促进癌症发展。然而，在临床环境中，G4s 与癌症相关的单核苷酸变异 (cSNVs) 之间的关系仍不清楚。在这项大规模研究中，我们整合了来自 13480 名癌症患者的实验验证的 G4s 和基因组 cSNVs，以研究 G4s 与细胞 cSNV 景观的空间关联。我们的研究结果表明，随着癌症患者局部 G4 含量的增加，局部基因组不稳定性增加，这表明 G4s 在驱动 cSNVs 方面可能具有潜在作用。值得注意的是，我们观察到 cSNVs 和常见单核苷酸变异 (dbSNVs) 与 G4s 之间存在不同的空间模式，这暗示了它们产生和积累的不同机制。我们进一步证明了 G4s 和 cSNVs 之间存在显著的、癌症特异性的差异，这可能对一类新的 G4 稳定癌症治疗方法具有重要意义。此外，我们表明高 G4 含量可以作为局部 cSNV 密度和患者生存率的预后标志物。我们的研究结果强调了在癌症研究中考虑 G4s 的重要性，并突出了需要进一步研究 G4 介导的基因组不稳定性的潜在分子机制，特别是在癌症背景下。
