Transcriptome of Anaplastic Thyroid Cancer Reveals Two Molecular Subtypes with Distinct Tumor Microenvironment and Prognosis.

Background

Although patients with anaplastic thyroid cancer (ATC) generally have a poor prognosis and there are currently no effective treatment options, survival and response to therapy vary between patients. Genomic and transcriptomic profiles of ATC have been reported; however, a comprehensive study of the tumor microenvironment (TME) of ATC is still lacking. This study aimed to elucidate the TME characteristics associated with ATC and their prognostic implications.

Methods

We analyzed bulk RNA transcriptomic data from 1,634 samples-including 476 normal thyroid tissues, 25 benign thyroid adenomas, 340 RAS-like and 719 BRAFV600E-like differentiated thyroid cancers (DTC-R and DTC-B, respectively), and 74 ATCs. We assessed the TME and molecular characteristics of these thyroid cancer subtypes using deconvolution analysis.

Results

The TME of ATC was characterized by a high abundance of immune cells and fibroblasts and a low abundance of epithelial cells compared to other thyroid histologies. During its malignant evolution, ATC exhibited an ecotype more closely related to DTC-B than RAS-like DTC (DTC-R). Furthermore, we identified two distinct molecular subtypes within ATC with significant differences in their TMEs. We termed the subtype with increased immune cells and fibroblasts as ATC-immune-fibroblast (ATC-IF) and the subtype with elevated epithelial and endothelial cells as ATC-epithelial-endothelial (ATC-E). The ATC-IF group had worse disease-specific survival (log-rank p = 0.035), higher ERK scores, and lower thyroid differentiation scores than the ATC-E group. While both ATC subtypes had elevated immune cells and fibroblasts compared to DTC-R and DTC-B, this increase was more pronounced in ATC-IF, with a marked rise in myeloid lineage cells and promigratory fibroblasts. Immune checkpoint gene expression and epithelial-mesenchymal transition scores were significantly higher in the ATC-IF group than in the ATC-E group.

Conclusion

ATC shows a TME distinct from that of DTC and can be further divided into two molecular subtypes-each with its own unique TME. The ATC-IF group, with a poorer prognosis and higher ERK score, is enriched in immune cells and fibroblasts, which may represent potential therapeutic targets.