High RAS Allele Frequency Signals Increased Risk of TERT Promoter Mutations in Thyroid Tumors

Area of Science:

• Oncology
• Genetics
• Molecular Diagnostics

Background:

• RAS mutations are common in thyroid cancer, typically indicating less aggressive behavior.
• Co-occurrence with TERT promoter mutations signifies poorer prognosis and increased tumor aggressiveness.
• RAS allele frequency (AF) may indicate clonal dominance and presence of high-risk mutations.

Purpose of the Study:

• To investigate the correlation between high RAS AF and the presence of TERT promoter mutations.
• To assess the association of RAS AF with other molecular alterations in thyroid nodules.

Main Methods:

• Retrospective analysis of 111 thyroid nodule patients with RAS mutations.
• Molecular testing using ThyroSeq v3 for RAS, TERT, copy number alterations (CNA), and gene expression profiles (GEP).
• Analysis of RAS AF in relation to TERT mutation status, nodule size, and other molecular findings.

Main Results:

• Nodules with both RAS and TERT mutations showed significantly higher mean RAS AF (38.1%) than RAS-only mutations (22.1%).
• Coexisting TERT mutations were associated with larger nodule size (3.7 cm vs. 2.4 cm).
• High RAS AF correlated with CNA and/or GEP positivity; GEP was positive in 100% of RAS/TERT co-mutated nodules.

Conclusions:

• Elevated RAS AF is linked to a higher probability of TERT promoter mutations and other genetic alterations.
• RAS AF serves as a valuable indicator for predicting coexisting high-risk mutations.
• Understanding RAS AF is important for optimizing thyroid cancer patient management.