Endocrinol Metab.  2023 Aug;38(4):445-454. 10.3803/EnM.2023.1702.

Different Molecular Phenotypes of Progression in BRAF- and RAS-Like Papillary Thyroid Carcinoma

• Lim J
• Lee HS
• Park J
• Kim KS
• Kim SK
• Cho YW
• Song YS

• KMID: 2545277
• DOI: http://doi.org/10.3803/EnM.2023.1702

Abstract

Background
Papillary thyroid carcinoma (PTC) can be classified into two distinct molecular subtypes, BRAF-like (BL) and RASlike (RL). However, the molecular characteristics of each subtype according to clinicopathological factors have not yet been determined. We aimed to investigate the gene signatures and tumor microenvironment according to clinicopathological factors, and to identify the mechanism of progression in BL-PTCs and RL-PTCs.
Methods
We analyzed RNA sequencing data and corresponding clinicopathological information of 503 patients with PTC from The Cancer Genome Atlas database. We performed differentially expressed gene (DEG), Gene Ontology, and molecular pathway enrichment analyses according to clinicopathological factors in each molecular subtype. EcoTyper and CIBERSORTx were used to deconvolve the tumor cell types and their surrounding microenvironment.
Results
Even for the same clinicopathological factors, overlapping DEGs between the two molecular subtypes were uncommon, indicating that BL-PTCs and RL-PTCs have different progression mechanisms. Genes related to the extracellular matrix were commonly upregulated in BL-PTCs with aggressive clinicopathological factors, such as old age (≥55 years), presence of extrathyroidal extension, lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and high metastasis-age-completeness of resection- invasion-size (MACIS) scores (≥6). Furthermore, in the deconvolution analysis of tumor microenvironment, cancer-associated fibroblasts were significantly enriched. In contrast, in RL-PTCs, downregulation of immune response and immunoglobulin-related genes was significantly associated with aggressive characteristics, even after adjusting for thyroiditis status.
Conclusion
The molecular phenotypes of cancer progression differed between BL-PTC and RL-PTC. In particular, extracellular matrix and cancer-associated fibroblasts, which constitute the tumor microenvironment, would play an important role in the progression of BL-PTC that accounts for the majority of advanced PTCs.

Keyword

Thyroid cancer, papillary; Transcriptome; Gene expression profiling; Tumor microenvironment

Figure

• 

  Fig. 1. Transcriptomic profiles of BRAF-like papillary thyroid carcinoma (BL-PTC) and RAS-like papillary thyroid carcinoma (RL-PTC) according to the clinicopathological factors. (A) Volcano plots showing differentially expressed genes (DEGs) of BL-PTCs (left) and RL-PTCs (right) between aggressive and indolent clinicopathological characteristics. (B) Venn diagrams displaying the number of overlapping and non-overlapping DEGs of BL-PTCs (red) and RL-PTCs (blue) according to the clinicopathological factors. ETE, extrathyroidal extension; LNM, lymph node metastasis; TNM, tumor-node-metastasis; MACIS, metastasis-age-completeness of resection-invasion-size.

• 

  Fig. 2. Enriched functional annotations of BRAF-like papillary thyroid carcinoma (BL-PTC) and RAS-like papillary thyroid carcinoma (RLPTC) according to the clinicopathological factors. Bubble charts showing the top 10 significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in (A) upregulated differentially expressed genes (DEGs) of BL-PTCs, (B) downregulated DEGs of all BL-PTCs (left) and BL-PTCs without thyroiditis (right), and (C) downregulated DEGs of all RL-PTCs (left) and RL-PTCs without thyroiditis (right). FDR, false discovery rate; ECM, extracellular matrix; RNAPII, RNA polymerase II; ETE, extrathyroidal extension; LNM, lymph node metastasis; TNM, tumor, node, metastasis; MACIS, metastasis-age-completeness of resection-invasion-size.

• 

  Fig. 3. Tumor microenvironment of BRAF-like papillary thyroid carcinoma (BL-PTC) and RAS-like papillary thyroid carcinoma (RL-PTC). (A) Extracellular matrix (ECM) score and (B) abundance of cancer-associated fibroblasts (CAFs) and normal fibroblasts in BL-PTCs (upper) and RL-PTCs (lower) between aggressive and indolent clinicopathological characteristics. ETE, extrathyroidal extension; LNM, lymph node metastasis; TNM, tumor, node, metastasis; MACIS, metastasis-age-completeness of resection-invasion-size; NS, not significant (P≥0.05). aP<0.05; bP<0.01; cP<0.001; dP<0.0001.

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