Mechanistic study of TFE3 breakage in TFE3-rearranged renal cell carcinoma: the perspective of non-canonical DNA structures and their stability

作者：Xiaopo Zhang, Q. Q. Dang, Xinghe Pan, Zhenggen Deng, Yanhao Xu, Weidong Gan, Hongqian Guo · 发表于：Frontiers in Genetics · 年份：2025 · DOI：10.3389/fgene.2025.1694739 · 研究领域：DNA Repair Mechanisms、Cancer Genomics and Diagnostics、Microtubule and mitosis dynamics

Background/Objectives To address the unelucidated mechanisms of breakpoint formation in TFE3 -rearranged renal cell carcinoma ( TFE3 -rRCC), this study characterizes breakpoint distribution within the TFE3 gene. We further explore how non-canonical DNA structures and their thermodynamic stability fluctuation may act as predisposing factors for the genomic instability driving these characteristic translocations. Methods TFE3 breakpoints were identified in a cohort of 31 TFE3 -rRCC tumor samples. The chi-square test was used to assess the statistical significance of breakpoint clustering. To investigate potential structural determinants, we predicted the distribution of G-quadruplex-forming sequences and palindromic motifs. Moving beyond simple motif density, we calculated the local Gibbs free energy changes ( ΔG ) associated with DNA secondary structures using Mfold and RNAfold to model thermodynamic stability across the TFE3 gene. This thermodynamic stability fluctuation was quantified as the maximum absolute local change in folding free energy (|d ΔG |). Finally, this correlation between thermodynamic stability fluctuation and breakpoint location was validated by analyzing the 13 most frequently rearranged genes reported in the COSMIC database. Results A significant breakpoint cluster was identified within intron 5 of TFE3 , containing 23 of 31 breakpoints (74.19%; chi-square test, P < 0.05). While the simple density of G-quadruplex or palindromic motifs did not direc...