Effect of Having Concurrent Mutations on the Degree of Aggressiveness in Patients with Thyroid Cancer Positive for TERT Promoter Mutations

SIMPLE SUMMARY: As molecular testing of thyroid nodules becomes more common, thyroid specialists must be able to interpret and understand the clinical implications of the results. A telomerase reverse transcriptase (TERT) promoter mutation can strongly predict thyroid cancer aggressiveness. However, the reason why some thyroid cancers with TERT promoter mutations are more aggressive than others remains unclear. This study aimed to examine whether TERT promoter mutations coexisting with other mutations are linked to more aggressive disease than TERT promoter mutations alone. The medical records of patients who had thyroid surgery and TERT promotor mutations were examined. Our findings showed that the likelihood of aggressive thyroid cancers was 10 times higher in patients with TERT promoter and other concurrent mutations. Thyroid specialists can use our results to accurately interpret the molecular testing of thyroid nodules, provide appropriate counseling, and discuss possible management options accordingly. ABSTRACT: This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals between 2017 and 2022 were reviewed. Twenty-four patients had TERT promoter mutations based on molecular profile testing. Clinicodemographic data, mutational profiles, and histopathological features were assessed. Descriptive analysis, Fisher’s exact test, and binary logistic regression were performed. Seven patients had single-gene TERT promoter mutations, and 17 had concurrent mutations, including BRAF V600E, HRAS, NRAS, PIK3CA, and EIF1AX. The overall prevalence of malignancy was 95.8%, of which 78.3% were aggressive thyroid cancers. There was a statistically significant association between concurrent mutations and disease aggressiveness. The odds of having aggressive disease were 10 times higher in patients with a TERT promoter mutation and a concurrent molecular alteration than in those with a TERT promoter mutation alone. This is an important finding for thyroid specialists to consider when counseling patients concerning risk stratification and management options.