Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence

Objectives. Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers re-main unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. Methods. This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam Na-tional University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. Results. Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer com-pared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tu-mor site, lymph node metastasis, and extrathyroidal extension). Conclusion. We identified a high association with immune-escape signaling in the immune-hot group with aggressive clini-cal characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for ad-vanced papillary thyroid cancer.

Automated summary

This study investigated the transcriptomic characteristics of advanced papillary thyroid cancer, revealing associations with immune-escape signaling, specific fusion genes, and a novel molecular biomarker for recurrence.