Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer

Fei Lin; Jiajia Huang; Wancui Zhu; Tongchao Jiang; Jia Guo; Wen Xia; Miao Chen; Ling Guo; Wuguo Deng; Huanxin Lin

doi:10.3389/fimmu.2023.1218987

Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer

Front Immunol. 2023 Jul 28:14:1218987. doi: 10.3389/fimmu.2023.1218987. eCollection 2023.

Authors

Fei Lin¹, Jiajia Huang¹, Wancui Zhu¹, Tongchao Jiang¹, Jia Guo¹, Wen Xia¹, Miao Chen¹, Ling Guo¹, Wuguo Deng¹, Huanxin Lin¹

Affiliation

¹ State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.

Abstract

Background: 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.

Methods: 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).

Results: 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 (P=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.

Conclusion: 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.

Keywords: immune infiltration; methylation; prognostic value; telomerase reverse transcriptase (TERT); triple negative breast cancer (TNBC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation
Humans
Prognosis
Protein Processing, Post-Translational
Telomerase* / genetics
Telomerase* / metabolism
Transcriptome
Triple Negative Breast Neoplasms* / metabolism
Tumor Microenvironment / genetics

Substances

TERT protein, human
Telomerase

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Grant No. 81773103) and the National Science Foundation for Young Scientists of China (Grant No.82102838).