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

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.

Papillary Thyroid Cancer Remodels the Genetic Information Processing Pathways

“…In total, the 39.0 Release of the National Cancer Institute GDC Data Portal (4 December 2023) lists 5869 mutations affecting 19,313 genes in the registered 1121 cases of thyroid cancer [15]. In addition to specific DNA mutations, regulation of the expression levels of selected gene sets were also pointed out as PTC transcriptomic signatures (e.g., [16][17][18]).…”

Papillary Thyroid Cancer Remodels the Genomic Fabrics of DNA Replication, Repair and Transcription

“…In addition to specific DNA mutations, regulation of the expression levels of selected gene sets were also pointed out as PTC transcriptomic signatures (e.g. [13][14][15]).…”