State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Immunol. 2023 Jul 28;14:1218987. doi: 10.3389/fimmu.2023.1218987. eCollection 2023.
Treatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy.
Data relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan-Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC).
Six DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients.
TERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.
由于缺乏有效的治疗靶点，三阴性乳腺癌（TNBC）患者的治疗选择仍然限于主要治疗方法。因此，迫切需要发现和鉴定治疗和诊断这种疾病的新的分子靶标。在这项研究中，我们分析了端粒酶逆转录酶（TERT）甲基化状态与 TERT 表达、预后和 TNBC 免疫浸润的相关性，并确定了 TERT 甲基化在调节 TNBC 预后和免疫治疗中的作用。
从癌症基因组图谱（TCGA）数据库中获取与 TNBC 患者的转录组、临床病理特征和甲基化相关的数据。检测 TERT 表达水平和差异甲基化位点（DMS）。计算 TERT 表达与 DMS 之间的相关性。绘制 Kaplan-Meier 曲线分析 TNBC 患者的生存与 DMS 之间的关系。评估 DMS 和 TERT 表达与免疫微环境的几种免疫特征（免疫细胞浸润、免疫调节剂、免疫相关生物途径和免疫检查点）之间的相关性。使用来自中山大学肿瘤防治中心（SYSUCC）的 40 名 TNBC 患者对结果进行验证。
鉴定出 6 个 DMS。其中，4 个位点（cg11625005、cg07380026、cg17166338 和 cg26006951）位于 TERT 启动子内，其中 2 个位点（cg07380026 和 cg26006951）与 TNBC 患者的预后显著相关。使用来自 SYSUCC 的 40 名 TNBC 样本的进一步验证表明，cg26006951 CpG 位点的高甲基化与不良生存预后相关（=0.0022）。TERT 表达与病理 N 期和临床分期显著相关，在 TCGA 队列中，cg07380026 与病理 T 和 N 期显著相关。此外，甲基化位点 cg26006951、cg07380026 和 TERT 表达与 TNBC 患者的免疫细胞浸润、常见免疫调节剂和免疫检查点受体淋巴细胞激活基因 3（LAG-3）水平显著相关。
TERT 启动子高甲基化在 TNBC 中调节 TERT 表达和肿瘤微环境中发挥重要作用。它与总生存期和 LAG-3 表达相关。TERT 启动子过度甲基化可能是预测 TNBC 患者对 TERT 抑制剂和免疫检查点抑制剂反应的潜在分子生物标志物。
