Endocrine Abstracts

Thyroid cells possess a strong reduction-oxidation (REDOX) mechanism that protects DNA from oxidative stress caused by elevated reactive oxygen species resulting from the synthesis of thyroid hormones and iodides derived from the iodination of thyroglobulin. SOD1, SOD2, GPX-1, G6PD, and CYBA encode important proteins involved in REDOX reactions. Their crucial roles in the promotion and progression of various types of cancers as well as their influence on pathways frequently activated in thyroid cancer are widely recognized. However, studies of thyroid tumors have yielded controversial results. To identify potential biomarkers and therapeutic targets, our group developed a strategy for a thorough analysis of the entire coding region of these genes by combining open-source bioinformatics techniques, publicly accessible datasets, and molecular quantum chemistry with multiple analysis algorithms, including 13 tools. In addition, we investigated the frequency of genetic alterations and their association with protein expression levels, and validated our results using large cancer biological databases (cBioPortal, OncoPrint, and PrognoScan). We collected 1.885 nsSNPs from the dbSNP database, including 223 for SOD1, 593 for SOD2, 324 for GPX1, 389 for G6PD, and 356 for CYBA. Eleven nsSNPs (8 in SOD1, 1 in GPX1, 1 in G6PD, and 1 in CYBA) consistently exhibited deleterious predictions across all 13 tools, demonstrating potential changes in protein function, structure, and stability, which can lead to perturbations in the REDOX balance. We further investigated the protein interaction network and signaling pathways observing a robust interaction between G6PD and other genes. G6PD expression positively affects the expression of TP53 and HRAS, making the gene a promising candidate for targeted therapy. Investigation of the frequency of genetic alterations and their association with protein expression levels has been hindered by the low mutation rate found in samples from patients with thyroid tumors in the CBioPortal database. Clinical databases indicate that SOD1, SOD2, GPX1, G6PD, and CYBA are associated with worse prognosis in several types of cancer, but our analysis did not reveal any significant impact on the survival of patients with thyroid cancer. Investigation of mRNA expression levels in the GEPIA database also did not show any impact of these genes on the overall survival of patients with thyroid cancer. In conclusion, we confirmed the important role of ROS in thyroid cancer etiopathogenesis, demonstrating that our bioinformatics pipeline is useful and may identify potential biomarkers of the risk and/or prognosis of thyroid cancer, as well as new therapeutic targets. One nsSNP, whose MAF is >0.5, may become a useful biomarker and is currently being validated in a large population of patients with thyroid cancer.