G-quadruplex-mediat ed g enomic instability driv es SNVs in cancer

Abstract

G-quadr uplex (G4s) DNA str uct ures ha v e been implicated in inducing genomic inst abilit y and contributing to cancer de v elopment. Ho w e v er, the relationship between G4s and cancer-related single nucleotide variants (cSNVs) in clinical settings remains unclear. In this large-scale study, w e integrated e xperimentally v alidated G4s with genomic cSNVs from 13480 cancer patients to in v estigate the spatial association of G4s with the cellular cSNV landscape. Our findings demonstrate an increase in local genomic inst abilit y with increasing local G4 content in cancer patients, suggesting a potential role for G4s in driving cSNVs. Notably, w e observ ed 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 ha v e important implications for a new class of G4-stabilizing cancer therapeutics. Moreo v er, w e sho w that high G4-content can serv e as a prognostic mark er f or local cSNV density and patient surviv al 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 inst abilit y, especially in the context of cancer.