Epigenetic Signature Discriminates Lymphatic Metastasis in BRAF Wild-Type Thyroid Carcinoma: Methylation Role of GRIK2

Abstract

Aim: Conservative treatment approaches for thyroid carcinoma (TC) patients with wild-type B-type Raf kinase (BRAF) pose risks of long-term recurrence. The association of DNA methylation with TC metastasis is unclear. Patients&methods: Here we analyzed data from 179 BRAF wild-type TC patients in the The Cancer Genome Atlas database, identifying significant metastasis-associated CpGs. A logistic regression model was developed and validated for discriminating lymphatic metastasis in BRAF wild-type TC. Results: The model showed high accuracy (AUC: 0.924 training set; 0.812 and 0.773 external cohorts). TAGLN, MRPL4, CLDN10 and GRIK2 emerged as diagnostic markers. GRIK2, downregulated due to promoter hypermethylation, acted as a TC suppressor. Conclusion: Our 5-CpG epigenetic signature effectively discriminates lymphatic metastasis in BRAF wild-type TC, highlighting GRIK2‘s tumor-suppressive role influenced by promoter hypermethylation.

Keywords::

• BRAF wild-type
• DNA methylation marker
• epigenetic signature
• GRIK2
• metastasis
• thyroid carcinoma

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2023-0334

J Peng, Q Zhang and F Lin contributed equally and share the first authorship. J Peng, Q Zhang, A Yang and X Su. conceived and designed the project. J Peng, Q Zhang, C Ke, W Deng, F Lin and X Su. performed the experiments and analyzed and interpreted the data. J Peng, Q Zhang, W Deng, F Lin and X Su. wrote and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank all members of W Deng’s 727 laboratory and A Yang’s 833 Laboratory for their advice and technical assistance.

Financial disclosure

This work was supported by the funds from the National Natural Science Foundation of China (82072981, 82272649), Natural Science Foundation of Guangdong Province (2019A1515010150) and Guangdong Basic and Applied Basic Research Foundation (2021A1515010083). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical disclosure

Clinical samples were obtained from the Tumor Bio-bank of Sun Yat-sen University Cancer Center. The study protocol for the SYSUCC cohort was approved by the Institutional Research Ethics Committee of Sun Yat-sen University Cancer Center (B2023-169-01). In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Materials.