Abstract
The chromosome 5p15.33 TERT-CLPTM1L region has been identified by genome-wide association studies as a susceptibility locus of multiple malignancies. However, the involvement of this locus in esophageal squamous cell carcinoma (ESCC) development is still largely unclear. We fine-mapped the TERT-CLPTM1L region through genotyping 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. After analyzing 2098 ESCC patients and frequency-matched 2150 unaffected controls, we found that rs2853691, rs2736100 and rs451360 genetic polymorphisms are significantly associated with ESCC risk in Chinese (all P<0.05). Reporter gene assays indicated that the ESCC susceptibility SNP rs2736100 locating in a potential TERT intronic promoter has a genotype-specific effect on TERT expression. Similarly, the CLPTM1L rs451360 SNP also showed allelic impacts on gene expression. After measuring TERT and CLPTM1L expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2736100 G risk allele carriers showed elevated oncogene TERT expression. Also, subjects with the rs451360 protective T allele had much lower oncogene CLPTM1L expression than those with G allele in tissue specimens. Results of these analyses underline the complexity of genetic regulation of telomere biology and further support the important role of telomerase in carcinogenesis. Our data also support the involvement of CLPTM1L in ESCC susceptibility.
Highlights
The chromosome 5p15.33 TERT-CLPTM1L region has been repeatedly proved to be a susceptibility locus of multiple malignancies according to genome-wide association studies (GWAS)
Reporter gene assays indicated that the esophageal squamous cell carcinoma (ESCC) susceptibility single nucleotide polymorphisms (SNPs) rs2736100 locating in a potential TERT intronic promoter has a genotype-specific effect on TERT expression
Logistic regression analyses revealed that rs2853691, rs2736100 and rs451360 SNPs were significantly associated with ESCC risk (Table 1)
Summary
The chromosome 5p15.33 TERT-CLPTM1L region has been repeatedly proved to be a susceptibility locus of multiple malignancies according to genome-wide association studies (GWAS). Independent susceptibility single nucleotide polymorphisms (SNPs) in this region were identified in lung cancer [1,2,3,4,5], melanoma [6], nonmelanoma skin cancer [7,8], glioma [9], bladder cancer [10], pancreatic cancer [11], testicular germ cell cancer [12], estrogen-negative breast cancer [13], ovarian cancer [14] and prostate cancer [15], suggesting that the region harbors several essential elements associating etiology of multiple cancers. The chromosome 5p15.33 region harbors two plausible candidate coding genes TERT and CLPTM1L. Activated TERT transcription in many cancers leads to increased telomerase activity to counteract telomere shortening and promotes malignant transformation of normal cells [17]. Accumulated evidences demonstrated that CLPTM1L may act as an oncogene in lung and pancreatic cancers [20,21,22]
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