The identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci.

// Liqing Zhou 1, 2, * , Guobin Fu 3, * , Jinyu Wei 1 , Juan Shi 1 , Wenting Pan 1 , Yanli Ren 1 , Xiangyu Xiong 1 , Jianhong Xia 2 , Yue Shen 2 , Hongliang Li 2 , Ming Yang 1 1 State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China 2 Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China 3 Department of Oncology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China * These authors have contributed equally to this work Correspondence to: Ming Yang, e-mail: yangm@mail.buct.edu.cn Keywords: TERT, CLPTM1L, polymorphism, esophageal squamous cell carcinoma, susceptibility Received: September 05, 2015     Accepted: December 07, 2015     Published: December 24, 2015 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.