Decoding the Mutational Hierarchy of Thyroid Cancer and Associated Signaling Pathways.

Area of Science:

• Genomics
• Oncology
• Endocrinology

Background:

• Thyroid cancer (TC) is the most common endocrine malignancy.
• Genomic alterations, particularly BRAF and RAS mutations, drive TC development.
• The complete mutational landscape of TC requires further elucidation.

Purpose of the Study:

• To systematically analyze the genomic landscape of thyroid cancer.
• To identify high-frequency driver genes and novel therapeutic targets.
• To clarify mutation hierarchy and cooperative pathways in TC.

Main Methods:

• Genome-wide analysis of 1,629 TC samples from TCGA and MSKCC via cBioPortal.
• Mutation frequency calculation and gene categorization into Tier I (>3%) and Tier II (<3%).
• Pathway and protein-protein interaction (PPI) network analysis.

Main Results:

• Identified 1,363 genes with >3% mutation frequency; Tier I included BRAF (56.9%), NRAS (9.3%), and TERT promoter (4.6%).
• Pathway analysis revealed enrichment in MAPK/ERK, PI3K-AKT signaling, and telomerase maintenance.
• Discovered mutual exclusivity between BRAF and RET alterations, suggesting pathway redundancy.

Conclusions:

• BRAF and RAS mutations are central to thyroid cancer oncogenesis.
• Under-explored genes in DNA repair and cell cycle pathways represent potential therapeutic targets.
• High frequency of TERT promoter mutations highlights their role in TC progression.