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

BACKGROUND/OBJECTIVES: mutations are among the most common genetic alterations in thyroid cancer and are generally associated with less aggressive behavior. However, when co-occurring with (telomerase reverse transcriptase) promoter mutations, known markers of poor prognosis, tumors exhibit markedly more aggressive features. The allele frequency (AF) of may serve as a potential indicator of clonal dominance and the likelihood of additional high-risk mutations, such as mutation. This study aims to assess whether a high AF correlates with the presence of coexisting promoter mutations and other molecular alterations.

METHODS

A retrospective chart review was performed on 111 patients with thyroid nodules harboring mutations, either alone or in combination with promoter mutations. All patients underwent molecular testing with ThyroSeq v3 and subsequent thyroidectomy at McGill University teaching hospitals. AF was analyzed in relation to mutation status, nodule size, and other molecular alterations including copy number alterations (CNA) and gene expression profiles (GEP).

RESULTS

The mean AF was significantly higher in nodules with both and mutations (38.1%) compared to those with mutations alone (22.1%) ( = 0.002). Nodules with coexisting mutations were also significantly larger (mean size: 3.7 cm vs. 2.4 cm; = 0.005). Malignant nodules, regardless of status, showed a trend toward higher AF than benign nodules (23.0% vs. 16.3%; = 0.052). Higher AF was also associated with the presence of CNA and/or GEP positivity. Notably, GEP was positive in 100% of nodules with both and mutations, compared to 37.5% in -only nodules ( = 0.002).

CONCLUSIONS

A high AF increases the likelihood of a promoter mutation and other genetic alterations, highlighting the importance of AF in optimizing patient care and management.