Abstract
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.
Highlights
Thyroid carcinoma is the most common endocrine malignancy and showed quickly increased incidence over last two decades
Rs2736100 genetic variant was associated with significantly elevated papillary thyroid carcinoma (PTC) risk (Table 2)
We systematically evaluated PTC susceptibility genetic variants in the TERT-CLPTM1L locus and their regulatory role in TERT gene expression ex vivo and in vivo
Summary
Thyroid carcinoma is the most common endocrine malignancy and showed quickly increased incidence over last two decades. According to the Chinese Cancer Registry, the incidence of thyroid carcinoma is 6.6 per 100,000 individuals in China[1,2]. Only a portion of exposed individuals develop PTC, suggesting that genetic factors may impact thyroid malignant transformation[4]. Accumulated evidences demonstrated that the chromosome 5p15.33 region (TERT-CLPTM1L) is a common susceptibility locus of multiple cancers. Considering the impacts of the 5p15.33 TERT-CLPTM1L locus on PTC susceptibility is still largely unknown, we examined the associations between 15 haplotype-tagging SNPs (htSNP) covering the entire TERT-CLPTM1L locus and PTC risk in three large independent case-control studies. To investigate the biological function of the PTC susceptibility TERT rs2736100 SNP, we examined impacts of its genotypes on TERT expression ex vivo and in vivo
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