TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer.

CONTEXT: Promoter mutations chr5:1,295,228C>T and chr5:1,295,250C>T (termed C228T and C250T, respectively) in the gene for telomerase reverse transcriptase (TERT) have been reported in various cancers and need to be further investigated in thyroid cancer.

OBJECTIVE: The aim of the study was to explore TERT promoter mutations in various thyroid tumors and examine their relationship with BRAF V600E mutation, iodine intake, and clinicopathological behaviors of thyroid cancer.

DESIGN: TERT promoter and BRAF mutations were identified by sequencing genomic DNA of primary thyroid tumors from normal- and high-iodine regions in China, and clinicopathological correlation was analyzed.

RESULTS: The C228T mutation was found in 9.6% (39 of 408) of papillary thyroid cancer (PTC), C250T was found in 1.7% (7 of 408) of PTC, and they were collectively found in 11.3% (46 of 408) of PTC. C228T was found in 31.8% (7 of 22) and C250T in 4.6% (1 of 22) of follicular thyroid cancer (FTC), and they were collectively found in 36.4% (8 of 22) of FTC. No TERT mutation was found in 44 benign thyroid tumors. The two mutations occurred in 3.8% (6 of 158) of BRAF mutation-negative PTC vs 16.0% (40 of 250) of BRAF mutation-positive PTC (P = 5.87 × 10(-4)), demonstrating their association. Unlike BRAF mutation, TERT promoter mutations were not associated with high iodine intake, but they were associated with older patient age, larger tumor size, extrathyroidal invasion, and advanced stages III/IV of PTC. Coexisting TERT and BRAF mutations were even more commonly and more significantly associated with clinicopathological aggressiveness.

CONCLUSIONS: In this large cohort, we found TERT promoter mutations to be common, particularly in FTC and BRAF mutation-positive PTC, and associated with aggressive clinicopathological characteristics.