TERT promoter methylation predicts overall survival, immune cell infiltration and response to immunotherapy in clear cell renal cell carcinoma.

IF 4.8 2区 医学 Q1 GENETICS & HEREDITY
Xinyu Guan, Jiahao Meng, Wenjun Yi, Kun Ye, Hongyu Gao, Yue Hong, Limeng Qu, Shirong Ding, Qian Long
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Abstract

Purpose: Telomerase reverse transcriptase (TERT) is one of the most well-established oncogenes in tumor development and progression. It is widely known that TERT promoter hypermethylation is associated with its transcription activation. Despite its canonical role in maintaining telomere length in cancer cells, TERT is also involved in various oncogenic processes independent of its enzymatic activity. However, the role of TERT in the tumor immune microenvironment has been largely unexplored. Hence, we assessed the associations between TERT promoter methylation and its expression, clinicopathological features, overall survival, immune cell infiltration, and response to immune checkpoint inhibitor therapy in clear cell renal cell carcinoma.

Methods: A single-sample gene-set enrichment analysis algorithm was used to quantify the relative abundance of each type of immune cell infiltration in the tumor microenvironment (TME) of the TCGA KIRC cohort. We used Spearman's rank correlation to calculate the correlation coefficients between TERT promoter methylation and immune cell infiltration. The relative methylation of cg11625005 in our validation cohort was detected by pyrosequencing and the relative infiltration of CD4 + and CD8 + T cells infiltration in the TME was measured by immunohistochemistry.

Results: The TERT promoter was significantly hypermethylated in clear cell renal cell tumor tissues, which was related to the transcriptional activation of TERT. TERT promoter hypermethylation was significantly correlated with aggressive phenotypes and poor survival in clear cell renal cell carcinoma patients. Furthermore, TERT promoter methylation was significantly positively correlated with CD4 + /CD8 + T cells infiltration and immune checkpoint molecule (CTLA-4, TIGIT, PD-1 and LAG3) expression. And TERT promoter methylation was correlated with the therapeutic response to anti-PD1 immunotherapy.

Conclusion: TERT promoter methylation is a promising predictive biomarker of immune cell infiltration, overall survival, clinicopathological characteristics and response to anti-PD1 immunotherapy treatment in clear cell renal cell carcinoma patients.

TERT启动子甲基化预测透明细胞肾细胞癌的总体生存、免疫细胞浸润和免疫治疗反应。
目的:端粒酶逆转录酶(TERT)是肿瘤发生发展过程中最明确的致癌基因之一。众所周知,TERT启动子超甲基化与其转录激活有关。尽管TERT在维持癌细胞端粒长度方面起着典型的作用,但它也参与各种独立于其酶活性的致癌过程。然而,TERT在肿瘤免疫微环境中的作用在很大程度上尚未被探索。因此,我们评估了透明细胞肾细胞癌中TERT启动子甲基化与其表达、临床病理特征、总体生存、免疫细胞浸润以及对免疫检查点抑制剂治疗的反应之间的关系。方法:采用单样本基因集富集分析算法,量化TCGA KIRC队列肿瘤微环境(TME)中各类型免疫细胞浸润的相对丰度。我们使用Spearman’s rank correlation计算TERT启动子甲基化与免疫细胞浸润之间的相关系数。通过焦磷酸测序检测验证队列中cg11625005的相对甲基化,免疫组织化学检测TME中CD4 +和CD8 + T细胞的相对浸润。结果:透明细胞肾细胞肿瘤组织中TERT启动子显著高甲基化,这与TERT的转录激活有关。在透明细胞肾细胞癌患者中,TERT启动子超甲基化与侵袭性表型和不良生存率显著相关。此外,TERT启动子甲基化与CD4 + /CD8 + T细胞浸润和免疫检查点分子(CTLA-4、TIGIT、PD-1和LAG3)表达显著正相关。TERT启动子甲基化与抗pd1免疫治疗的治疗反应相关。结论:TERT启动子甲基化是透明细胞肾癌患者免疫细胞浸润、总生存、临床病理特征和抗pd1免疫治疗反应的一个有前景的预测性生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
自引率
5.30%
发文量
150
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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