Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, 226007, India.
Icahn School of Medicine at Mount Sinai, New York, 10029, USA.
J Cancer Res Clin Oncol. 2023 Nov;149(16):15159-15170. doi: 10.1007/s00432-023-05305-w. Epub 2023 Aug 27.
The MGMT (O-methylguanine-DNA methyltransferase) gene plays a crucial role in repairing DNA damage caused by alkylating agents, including those used in chemotherapy. Genetic and epigenetic alterations can influence the regulation of MGMT gene, which in turn may impact the response to concomitant chemoradiotherapy (CRT) in cervical cancer. The present study was undertaken to evaluate the correlation of such variations in MGMT gene with the treatment outcome of concomitant chemoradiotherapy (CRT) in cervical cancer.
A total of 460 study subjects (240 controls and 220 patients) were subjected to genotypic analysis of MGMT gene variants rs12917(T/C) and rs2308327(A/G) by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Out of them, 48 each of controls and patients were analyzed for promoter methylation and expression by methylation-specific PCR and real-time PCR, respectively. Patients (n = 48) were followed up and evaluated for treatment (CRT) outcome. Statistical analyses were done using GraphPad (9.0) and SPSS version 18.0.
Individuals with GG genotype, G allele of rs2308327, and haplotype 'TA' of both variants showed a significant increase in the development of cervical cancer (P ≤ 0.05). In epigenetic regulation, there was a significant hypermethylation of MGMT gene and down-regulation of their expression in patients compared to control individuals. In treatment outcome of CRT, GG genotype of rs2308327(A/G) gene variant showed better response and GG + AG was significantly associated with vital status (alive). Unmethylated MGMT gene showed better median overall survival up to 25 months significant in comparison to methylated MGMT promoter.
Gene variant rs2308327(A/G) and promoter hypermethylation regulated MGMT gene can be a good prognostic for treatment response in cervical cancer patients.
MGMT（O-甲基鸟嘌呤-DNA 甲基转移酶）基因在修复烷基化剂引起的 DNA 损伤方面发挥着至关重要的作用，包括那些在化疗中使用的药物。遗传和表观遗传的改变会影响 MGMT 基因的调控，进而可能影响宫颈癌同步放化疗（CRT）的反应。本研究旨在评估 MGMT 基因中的这些变异与宫颈癌同步放化疗（CRT）治疗结果的相关性。
共对 460 例研究对象（240 例对照和 220 例患者）进行 MGMT 基因 rs12917（T/C）和 rs2308327（A/G）基因变异的扩增受阻突变系统-聚合酶链反应（ARMS-PCR）的基因分型分析。其中，分别对 48 例对照和患者进行启动子甲基化和表达的甲基特异性 PCR 和实时 PCR 分析。对患者（n=48）进行随访并评估治疗（CRT）结果。使用 GraphPad（9.0）和 SPSS 版本 18.0 进行统计分析。
携带 GG 基因型、rs2308327 的 G 等位基因和两个变异的“TA”单倍型的个体患宫颈癌的风险显著增加（P≤0.05）。在表观遗传调控方面，与对照个体相比，MGMT 基因发生显著的超甲基化和表达下调。在 CRT 治疗结果中，rs2308327（A/G）基因变异的 GG 基因型显示出更好的反应，GG+AG 与生存状态（存活）显著相关。未甲基化的 MGMT 基因在中位总生存时间上表现出更好的效果，与甲基化的 MGMT 启动子相比可达 25 个月。
rs2308327（A/G）基因变异和启动子的高甲基化调节 MGMT 基因可能是宫颈癌患者治疗反应的良好预后指标。
