Telomerase in differentiated thyroid cancer: promoter mutations, expression and localization

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Telomerase-reverse-transcriptase (TERT) promoter mutations are emerging as significant factors in various cancers.
• Their role in differentiated thyroid cancers (DTCs) requires further elucidation.

Purpose of the Study:

• To investigate the prevalence and prognostic significance of TERT promoter mutations in papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC).
• To compare the prognostic value of TERT mutations with established markers like BRAF(V600E) and RAS.
• To analyze TERT protein expression and cellular localization in relation to mutation status and clinical outcome.

Main Methods:

• Analysis of TERT promoter mutations in a large series of PTC and FTC cases.
• Correlation of mutation status with clinicopathological features, age at diagnosis, and patient outcome.
• Western blot (WB) analysis for TERT protein expression.
• Immunohistochemistry (IHC) for TERT protein localization in tumor and normal tissues.

Main Results:

• TERT mutations were identified in 12% of PTCs and 14% of FTCs, significantly associated with older age and poorer outcomes.
• TERT mutations demonstrated a stronger prognostic value than BRAF(V600E) mutations.
• Coexistent TERT mutations with BRAF (in PTCs) or RAS (in FTCs) did not alter the outcome compared to isolated TERT mutations.
• TERT protein expression was significantly higher in tumor tissues than in normal tissues, especially in mutated cases.
• TERT protein showed predominantly cytoplasmic localization in tumors and metastatic lymph nodes, unlike normal tissue where it was equally distributed between nucleus and cytoplasm.

Conclusions:

• TERT promoter mutations are significant negative prognostic markers in differentiated thyroid tumors, independent of BRAF or RAS mutations.
• Increased TERT protein expression and altered cytoplasmic localization in tumors suggest a potential role in thyroid cancer progression through non-canonical mechanisms.