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 remain 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 National
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 compared 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 (
tumor size,
lymph node metastasis, and extrathyroidal extension). @*Conclusion@#. We identified a high
association with immune-escape signaling in the immune-hot group with aggressive clinical 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 advanced
papillary thyroid cancer.