The relationship between telomerase reverse transcriptase promoter rs2853669 allele C accompanied by C228T and the grade of thyroid malignancy.

91 Background: Two-point mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) gene are considered molecular indicators of adverse thyroid tumor biology. The regulatory single nucleotide polymorphism rs2853669 (TrSNP) is located near these TERT promoter mutations and its association with the grade of various cancers has been recently reported. To clarify whether the TrSNP can be a clinically useful molecular marker, we analyzed the relationship of the TrSNP with tumor growth and malignant potential in papillary thyroid cancer and follicular tumors. Methods: DNA was extracted from blood and FFPE specimens of 218 patients with thyroid tumors (133 papillary and 85 follicular), and TrSNP, C228T, and C250T were analyzed. BRAFV600E and NRAS Q61R mutations were also analyzed. The association of these genotypes and mutations with clinicopathological parameters were investigated. Results: The C allele of TrSNP from blood and FFPE specimens were validated with 97.3% concordance, so the C allele of TrSNP from blood samples were used in this study. Univariate analysis of 133 papillary carcinomas for clinicopathologic features showed that the C allele of TrSNP significantly correlated with tumor size as did the C228T mutation (p<0.05, p<0.001). Co-expression of the TrSNP and C228T were significantly corelated with tumor size, extrathyroidal invasion and lymph nodal metastasis (p<0.01, p<0.05). Eighty-five follicular tumors (19 follicular carcinomas and 66 follicular adenomas) were examined. Univariate analysis showed no significant association between the C allele of TrSNP, C228T, or C250T and tumor size. Multivariate analysis demonstrated the C allele TrSNP and C228T were significantly frequent in follicular carcinoma (p<0.05, p<0.001) and therefore were considered a risk factor for malignancy. Conclusions: This study demonstrates that the C-allele of the TrSNP is an indicator of tumor growth of papillary carcinoma and co-expression of the TrSNP and C228T relate tumor progression and malignant grade. These genetic features are expected to be a useful molecular marker for differential diagnosis of benign and malignant tumors and for determining treatment strategies.