Huang Liming, Xu Wenshen, Yan Danfang, Shi Xi, Zhang Shu, Chen Meiqin, Dai Lian
Department of Oncology, The Affiliated People's Hospital, Fujian University of Traditional Chinese Medicine, #602 Bayiqizhong Road, Fuzhou, 350004, China.
Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
Cancer Cell Int. 2023 Oct 19;23(1):246. doi: 10.1186/s12935-023-03100-8.
RAD51B plays a significant role in homologous recombination-mediated repair of DNA double-strand breaks. Many enhancer variants are involved in cancer development and progression. However, the significance of enhancer variants of RAD51B in glioma susceptibility and progression remains unclear.
A case-control study consisting of 1056 individuals was conducted to evaluate the associations of enhancer variants of RAD51B with glioma susceptibility and progression. Sequenom MassARRAY technology was used for genotyping. The function of enhancer variants was explored by biochemical assays.
A significantly decreased risk of glioma was associated with rs6573816 GC genotype compared with rs6573816 GG genotype (OR = 0.66, 95% CI 0.45-0.97; P = 0.034). Multivariable Cox regression revealed that rs6573816 was significantly associated with glioma progression in a sex-dependent manner. Worse PFS was found in the male patients with high grade glioma carrying rs6573816 GC or CC genotype (HR = 2.28, 95% CI 1.14-4.57; P = 0.020). The rs6573816 C allele repressed enhancer activity by affecting transcription factor POU2F1 binding, which resulted in lower expression of RAD51B. Remarkably attenuated expression of RAD51B was observed following POU2F1 knockdown. Consistently, positive correlation between the expression of POU2F1 and RAD51B was found in lymphoblastic cells and glioma tissues.
These results indicate that an enhancer variant of RAD51B rs6573816 influences enhancer activity by changing a POU2F1 binding site and confers susceptibility and progression to glioma.
RAD51B在DNA双链断裂的同源重组介导修复中起重要作用。许多增强子变异体参与癌症的发生和发展。然而，RAD51B增强子变异体在胶质瘤易感性和进展中的意义仍不清楚。
进行了一项包含1056名个体的病例对照研究，以评估RAD51B增强子变异体与胶质瘤易感性和进展的关联。采用Sequenom MassARRAY技术进行基因分型。通过生化分析探索增强子变异体的功能。
与rs6573816 GG基因型相比，rs6573816 GC基因型与胶质瘤风险显著降低相关（OR = 0.66，95% CI 0.45 - 0.97；P = 0.034）。多变量Cox回归显示，rs6573816以性别依赖的方式与胶质瘤进展显著相关。携带rs6573816 GC或CC基因型的高级别胶质瘤男性患者的无进展生存期较差（HR = 2.28，95% CI 1.14 - 4.57；P = 0.020）。rs6573816 C等位基因通过影响转录因子POU2F1结合来抑制增强子活性，从而导致RAD51B表达降低。在敲低POU2F1后，观察到RAD51B表达明显减弱。一致地，在淋巴细胞和胶质瘤组织中发现POU2F1和RAD51B表达呈正相关。
这些结果表明，RAD51B的增强子变异体rs6573816通过改变POU2F1结合位点影响增强子活性，并赋予胶质瘤易感性和进展性。
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