Table 3. Summary of clinically relevant clinicopathologic implications of BRAF, RAS and TERTp gene mutations in follicular-cell derived thyroid tumors (adapted from De Leo et al. (2024)).

Genes	Molecular pathology	Thyroid tumor type	Clinical and pathological implications
A. Summary of clinically relevant clinicopathologic implications of BRAF gene mutations in follicular-cell derived thyroid tumors (adapted from De Leo et al. (2024)).
BRAF	BRAF is a serine/threonine kinase of the MAPK signaling pathway that regulates cell differentiation, proliferation, and survival	Papillary carcinoma (40–80%) : BRAF p.V600E is more frequent in conventional papillary carcinoma, i.e., classic papillary carcinoma and other subtypes, except the Encapsulated follicular variant of papillary carcinoma that belongs to the RAS-like mutated group	BRAF p.V600E is used as a diagnostic marker for preoperative fine needle aspiration in molecular typing of cytologically indeterminate thyroid nodules
	Activating mutations
	Hotspot mutations in exon 15; the most common substitution (95% of cases) is c.1799 T > A (p.V600E). BRAF p.V600E is the prototype of the BRAF p.V600E-like tumor group (2014 TCGA molecular classification scheme)	High-grade non-anaplastic carcinoma of follicular cells: high-grade papillary carcinoma, often belonging to aggressive papillary carcinoma subtypes (e.g., tall cell, hobnail) (<5%)	Prognosis: BRAF p.V600E has been linked to extra thyroid extension and to an increased risk of PTC recurrence. However, its overall relevance for risk stratification is probably limited when other parameters like stage and histologic typing are taken into account
		PDTC (<5%)
	Other mutations include c.1801A > G (p.K601E) and small deletions or insertions close to codon 600; these mutations generally are present in the RAS-like mutated tumor group (2014 TCGA molecular classification scheme).	Anaplastic carcinoma (35%)	Therapy: Anaplastic and aggressive radioactive iodide refractory BRAF p.V600E mutated thyroid carcinomas respond to a combination of RAF and MEK kinase inhibitors
	AKAP9: BRAF	Papillary carcinomas that are radiation-induced that develop more frequently in children
B. Summary of clinically relevant clinicopathological implications of RAS genes mutations in follicular-cell derived thyroid tumors (adapted from De Leo et al. (2024)).
RAS	HRAS, KRAS, and NRAS are G-proteins that have a critical role in the intracellular transduction of signals from the cell membrane.	Follicular adenoma (20–40%)	RAS mutations can be present in any follicular patterned thyroid nodule or tumor
		Follicular carcinoma (30–50%)
	In tumors of follicular cells, mutations most frequently affect NRAS codon 61.	Encapsulated follicular variant papillary carcinoma, invasive and non-invasive (i.e., NIFTP) (25–45%)	The presence of clonal RAS mutation is considered a molecular evidence of neoplasm, but may be present in a small number of histologically hyperplastic nodules of follicular nodular disease/multinodular hyperplasia/thyroid goiter
		Poorly differentiated carcinoma (20–50%)
	RAS mutations are the prototype of the RAS-like mutated tumor group (2014 TCGA molecular classification scheme)	Anaplastic carcinoma (10–50%)
		Medullary carcinoma (10–20% of sporadic cases, rare in cases with germline RET mutation)	RAS mutations are used in preoperative cytology via FNA, particularly in indeterminate thyroid nodules.
			RAS mutations indicate that the nodule is neoplastic, but not necessarily malignant, being most RAS-mutated nodules diagnosed as benign after surgery: hyperplastic nodule, follicular adenoma, or NIFT
C. Summary of relevant clinicopathological implications of TERTp genes mutations in follicular-cell derived thyroid tumors (adapted from De Leo et al. (2024)).
TERT	TERT is expressed in germ cells and somatic stem cells. It is not normally expressed (or is expressed at very low levels) in most somatic cells.	Follicular carcinoma (10–35%)	“Late” molecular event associated with tumor progression
		Papillary carcinoma, conventional (5–15%)	TERT promoter mutations are clonal and highly prevalent in aggressive carcinomas, while they are uncommon and often subclonal in conventional papillary and follicular carcinoma.
		Encapsulated follicular variant papillary carcinoma (5–15%)
	TERT C228T (hotspot position −124) is much more common than TERT C250T (hotspot position −126).	High-grade non-anaplastic carcinoma of follicular cells (20–50%), equally common in poorly differentiated carcinoma and high-grade papillary carcinoma
	Mutations create a novel binding site for transcription factors of the ETS family, which increase TERT transcription and telomerase expression	Anaplastic carcinoma (30–75%)	Some studies indicate that tumors with concomitant presence of TERT promoter and with RAS and BRAF p.V600E mutation have worse prognosis
			Powerful indicator of poor prognosis and risk for distant metastasis in carcinomas of follicular cells, independent of histologic typing/subtyping and other relevant clinicopathologic parameters