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TERT is the catalytic subunit of telomerase which plays an essential part in cellular immortality by maintaining telomere integrity. TERT is commonly over-expressed in human malignancies, indicating its key role in cell transformation. The chromosome 5p15.33  TERT-CLPTM1L  region has been associated with susceptibility of multiple cancers via a genome-wide association approach. However, the involvement of this locus in papillary thyroid carcinoma (PTC) etiology is still largely unknown. We analyzed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) of the  TERT - CLPTM1L  region in a two stage case-control design. After genotyping 2300 PTC patients and frequency-matched 2300 unaffected controls, we found that  TERT  rs2736100 genetic variant is significantly associated with elevated PTC risk.  Ex vivo  reporter gene assays indicated that the PTC susceptibility rs2736100 polymorphism locating in a potential  TERT  intronic enhancer has a genotype-specific effect on  TERT  expression. Correlations between rs2736100 genotypes and tissue-specific  TERT  expression supported the regulatory function of this genetic variant  in vivo . Our data demonstrated that the functional  TERT  rs2736100 SNP as a novel genetic component of PTC etiology. This study, together with recent studies in other cancers, unequivocally establishes an essential role of TERT in cancers.

Functional evaluation of TERT-CLPTM1L genetic variants associated with susceptibility of papillary thyroid carcinoma