Abstract
OBJECTIVE: The primary objective of this study is to conduct a comprehensive screening and analysis of differentially expressed genes related to disulfidoptosis (DEDRGs) in thyroid carcinoma (THCA). This entails delving into the intricate characterization of immune cell infiltration within the THCA context and subsequently formulating and validating a novel prognostic model. METHOD: To achieve our objectives, we first delineated two distinct subtypes of disulfidoptosis-related genes (DRGs) via consensus clustering methodology. Subsequently, employing the limma R package, we identified the DEDRGs critical for our investigation. These DEDRGs underwent meticulous validation across various databases, alongside an in-depth analysis of gene regulation. Employing functional enrichment techniques, we explored the potential molecular mechanisms underlying disulfidoptosis in THCA. Furthermore, we scrutinized the immune landscape within the two identified subtypes utilizing CIBERSORT and ESTIMATE algorithms. The construction of the prognostic model for THCA entailed intricate methodologies including univariate, multivariate Cox regression, and LASSO regression algorithms. The validity and efficacy of our prognostic model were corroborated through Kaplan-Meier survival curves and ROC curves. Additionally, a nomogram was meticulously formulated to facilitate the prediction of patient prognosis. To fortify our findings, we conducted a comprehensive Bayesian co-localization analysis coupled with rigorous in vitro experimentation, aimed at unequivocally establishing the validity of the identified DEDRGs. RESULT: Our analyses unveiled Cluster C1, characterized by elevated expression levels of DEDRGs, as harboring a favorable prognosis accompanied by abundant immune cell infiltration. Correlation analyses underscored predominantly positive associations among the DEDRGs, further affirming their significance in THCA. Differential expression patterns of DEDRGs between tumor samples and normal tissues were evident across the GEPIA and HPA databases. Insights from the TIMER database underscored a robust correlation between DEDRGs and immune cell infiltration. KEGG analysis elucidated the enrichment of DEDRGs primarily in pivotal pathways including MAPK, PPAR signaling pathway, and Proteoglycans in cancer. Furthermore, analyses using CIBERSORT and ESTIMATE algorithms shed light on the crucial role played by DEDRGs in shaping the immune microenvironment. The prognostic model, anchored by five genes intricately associated with THCA prognosis, exhibited commendable predictive accuracy and was intricately linked to the tumor immune microenvironment. Notably, patients categorized with low-risk scores stood to potentially benefit more from immunotherapy. The validation of DEDRGs unequivocally underscores the protective role of INF2 in THCA. CONCLUSION: In summary, our study delineates two discernible subtypes intricately associated with DRGs, revealing profound disparities in immune infiltration and survival prognosis within the THCA milieu. The implications of our findings extend to potential treatment strategies for THCA patients, which could entail targeted interventions directed towards DEDRGs and prognostic genes, thereby influencing disulfidptosis and the immune microenvironment. Moreover, the robust predictive capability demonstrated by our prognostic model, based on the five genes (ANGPTL7, FIRRE, ODAPH, PROKR1, SFRP5), underscores its potential clinical utility in guiding personalized therapeutic approaches for THCA patients.