Research Paper Volume 16, Issue 7 pp 6488—6509
Multidimensional data analysis revealed thyroiditis-associated TCF19 SNP rs2073724 as a highly ranked protective variant in thyroid cancer
- 1 Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
- 2 Department of Head and Neck Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian, China
- 3 Thyroid-Otolaryngology Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610000, Sichuan, China
- 4 Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin 300121, China
- 5 Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin 300121, China
- 6 Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
Received: November 24, 2023 Accepted: March 14, 2024 Published: April 4, 2024
https://doi.org/10.18632/aging.205718How to Cite
Copyright: © 2024 Ruan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear.
Results: In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer. Our analyses revealed significant associations between TCF19 and various autoimmune diseases and human cancers, including cervical cancer and autoimmune thyroiditis, with a particularly robust signal for the deleterious missense variation rs2073724 that is associated with thyroid function, hypothyroidism, and autoimmunity. Furthermore, functional assays and transcriptional profiling in thyroid cancer cells demonstrated that TCF19 regulates important biological processes, especially inflammatory and immune responses. We demonstrated that TCF19 could promote the progression of thyroid cancer in vitro and in vivo and the C>T variant of rs2073724 disrupted TCF19 protein binding to target gene promoters and their expression, thus reversing the effect of TCF19 protein.
Conclusions: Taken together, these findings implicate TCF19 as a promising therapeutic target in aggressive thyroid malignancies and designate rs2073724 as a causal biomarker warranting further investigation in thyroid cancer.
Abbreviations
TCF19: the transcription factor 19; GWAS: genome-wide association study; PheWAS: phenome-wide association study; HER: electronic health record; SIFT: Sorting Intolerant from Tolerant; TCGA: The Cancer Genome Atlas; RT-Qpcr: quantitative reverse transcription PCR; PFIs: progression-free intervals; RNA-seq: RNA sequencing; DEGs: differentially expressed genes; TME: tumour microenvironment; TIDE: Tumour Immune Dysfunction and Exclusion; ChIP: chromatin immunoprecipitation; FHA: forkhead association.