Decoding the Mutational Hierarchy of Thyroid Cancer and Associated Signaling Pathways

Thyroid cancer (TC) is the most prevalent endocrine malignancy, and its development is influenced by various genomic abnormalities. Activating mutations in oncogenes such as BRAF and RAS significantly contribute to tumorigenesis. Nevertheless, the overall mutational landscape of TC remains unclear.

We conducted a systematic analysis of genomic data from 1,629 TC samples across four independent studies (including TCGA and MSKCC) available on the cBioPortal platform. We calculated mutation frequencies for all genes and categorized those exceeding a 3% threshold as high-frequency driver genes (Tier I) and genes with moderate mutation rates (Tier II).

A total of 1,363 genes exhibited mutation frequencies above 3% within the TC cohort. Tier I genes included BRAF (56.9%), NRAS (9.3%), TERT promoter (4.6%), HRAS (3.5%), and TTN (3.2%), with BRAF^V600E. Tier II featured 19 genes, such as TG (2.9%), linked to follicular carcinogenesis, and TP53 (2.7%), associated with poorly differentiated subtypes. Pathway analysis revealed enrichment in MAPK/ERK signaling, PI3K-AKT activation, and telomerase maintenance. PPI networks identified lesser-studied interactors involved in DNA repair and cell cycle regulation, suggesting new therapeutic targets. Among the 1,620 patients with TC, females predominated and the peak incidence occurred in middle adulthood. This study illustrates a strong mutual exclusivity between BRAF and RET alterations, with minimal co-occurrence, indicating functional redundancy through shared MAPK/ERK and PI3K/AKT signaling pathways.

The present study clarifies the mutation hierarchy and cooperative pathways in TC, underscoring the significance of BRAF- and RAS-driven oncogenesis. The discovery of under-explored genes within DNA damage response and cell cycle networks paves the way for targeted therapy development. Furthermore, the high frequency of TERT promoter mutations emphasizes their role in disease progression.