Background/Objectives:
RAS mutations are among the most common genetic alterations in thyroid cancer and are generally associated with less aggressive behavior. However, when co-occurring with
TERT (telomerase reverse transcriptase) promoter mutations, known markers of poor prognosis, tumors exhibit markedly more aggressive features. The allele frequency (AF) of
RAS may serve as a potential indicator of clonal dominance and the likelihood of additional high-risk mutations, such as
TERT mutation. This study aims to assess whether a high
RAS AF correlates with the presence of coexisting
TERT promoter mutations and other molecular alterations. Methods: A retrospective chart review was performed on 111 patients with thyroid nodules harboring
RAS mutations, either alone or in combination with
TERT promoter mutations. All patients underwent molecular testing with ThyroSeq v3 and subsequent thyroidectomy at McGill University teaching hospitals.
RAS AF was analyzed in relation to
TERT mutation status, nodule size, and other molecular alterations including copy number alterations (CNA) and gene expression profiles (GEP). Results: The mean
RAS AF was significantly higher in nodules with both
RAS and
TERT mutations (38.1%) compared to those with
RAS mutations alone (22.1%) (
p = 0.002). Nodules with coexisting
TERT mutations were also significantly larger (mean size: 3.7 cm vs. 2.4 cm;
p = 0.005). Malignant nodules, regardless of
TERT status, showed a trend toward higher
RAS AF than benign nodules (23.0% vs. 16.3%;
p = 0.052). Higher
RAS AF was also associated with the presence of CNA and/or GEP positivity. Notably, GEP was positive in 100% of nodules with both
RAS and
TERT mutations, compared to 37.5% in
RAS-only nodules (
p = 0.002). Conclusions: A high
RAS AF increases the likelihood of a
TERT promoter mutation and other genetic alterations, highlighting the importance of
RAS AF in optimizing patient care and management.
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