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Risk stratification by combining common genetic mutations and TERT promoter methylation in papillary thyroid cancer

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Abstract

Purpose

Risk stratification based on somatic mutations in TERT promoter and BRAF/RAS has been well established for papillary thyroid cancer (PTC), and there is emerging evidence showed that TERT promoter methylation was frequently observed in thyroid cancer patients with adverse features. This study was aimed to comprehensive explore the prognostic value of BRAF/RAS mutations, TERT promoter mutations, and TERT promoter methylation in PTC.

Methods

The relationships of BRAF/RAS mutations, TERT promoter mutations, and TERT promoter methylation with clinical characteristics and outcomes of PTC were analyzed in 382 patients with PTC.

Results

TERT promoter mutation and hypermethylation were collectively observed in 52 (13.6%) samples and associated with BRAF/RAS mutation, aggressive clinical characteristics, and poor clinical outcomes of PTC. Coexistence of BRAF/RAS and TERT alterations was found in 45 of 382 (11.8%) PTC patients and strongly associated with old patient age, extrathyroidal extension, advanced pathologic T stage and metastasis. Importantly, patients with both BRAF/RAS and TERT alterations had higher rates of tumor recurrence (13.6% vs 1.5%, P = 0.042) and disease progression (24.4% vs 3.3%, P < 0.001) than patients without any alterations, and cox regression analysis revealed that the coexistence of BRAF/RAS and TERT alterations, but not BRAF/RAS or TERT alterations alone, increased the risk of progression-free interval with an adjusted HR of 10.35 (95% CI: 1.79–59.81, P = 0.009).

Conclusions

This study suggested that comprehensively analysis of BRAF/RAS mutations, TERT promoter mutation and methylation is an effective strategy to identify high-risk patients with PTC.

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Data availability

Publicly available TCGA thyroid cancer datasets analyzed in this study can be found at https://portal.gdc.cancer.gov/ or https://xena.ucsc.edu/. Further specific inquiries can be directed to the corresponding author.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 82072952 and No. 82222051) and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (No. 22ykqb05).

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Authors and Affiliations

  1. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, China

    Ye Sang, Guanghui Hu, Mengke Chen & Rengyun Liu

  2. Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, China

    Junyu Xue & Shubin Hong

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Contributions

R.L. and Y.S. designed the research; Y.S., G.H., J.X., M.C., and S.H. collected the data; Y.S., G.H., J.X., and R.L. analyzed the data; R.L. and Y.S. drafted the manuscript, with inputs from all authors. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Rengyun Liu.

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Sang, Y., Hu, G., Xue, J. et al. Risk stratification by combining common genetic mutations and TERT promoter methylation in papillary thyroid cancer. Endocrine (2024). https://doi.org/10.1007/s12020-024-03722-6

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