Association of TERT-CLPTM1L and 8q24 Common Genetic Variants with Gallbladder Cancer Susceptibility and Prognosis in North Indian Population
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Gallbladder carcinoma (GBC) is one of the common malignancy of the biliary tract. Several genome wide and candidate gene studies have reported associations between multiple cancer types and single-nucleotide polymorphisms on 5p15.33 and 8q24.21 loci. However, predisposition potential of these genetic variants has not been assessed in GBC. We performed the present study to assess the potential of five polymorphisms on 5p15.33 and one on 8q24.21 locus in GBC risk and treatment response in patients undergoing chemoradiotherapy. We extracted genomic DNA from peripheral blood and genotyped selected SNPs using TaqMan allelic discrimination assays in 523 GBC cases and 274 controls from the north-Indian population. Statistical tests were performed to assess the association of selected common genetic variants with gallbladder cancer susceptibility and prognosis. Binary logistic regression analysis showed significant association of TERT rs2736100C > A [OR(CI) = 0.690(0.515–0.924), p value = 0.013], CLPTM1L rs401681C > T [OR(CI) = 0.586(0.405–0.847), p value = 0.004], and CASC8 rs6983267G > T [OR(CI) = 1.629(1.215–2.186), p value = 0.001] with GBC risk. Further, using multivariate logistic regression, we observed that haplotype CLPTM1L Crs401681Crs31489 TERT Trs2853676Ars2736100 MIR4457 Grs4635969 [OR(CI) = 7.52 (1.79–31.52), p value = 0.0064] is significantly associated with poor treatment response. In survival analysis, Kaplan–Meier survival curves showed significantly poor survival and COX regression suggested significantly higher hazard ratio in TT genotype carriers of CASC8 rs6983267 [OR(CI) = 4.28(1. 07–17.10), p value = 0.040] as compared to major allele and heterozygous (GG+GT) genotypes in metastatic GBC cases. The study revealed that 5p15.33 and 8q24.21 genetic variants significantly influence GBC risk and treatment response in north-Indian population.
KeywordsGallbladder carcinoma/neoplasms Biliary tract cancer/neoplasms Telomerase Genetic predisposition Genetic association studies TERT rs2853676 rs2736100 CLPTM1L rs401681 rs31489 MIR4457 rs4635969
Funding was provided by Department of Biotechnology, Ministry of Science and Technology (Grant No. BT/PR15017/MED/12/498/2010).
SY and BM designed the study, analyzed the data, and drafted the manuscript. SY performed experiments, and AC, AK, and BM provided necessary logistical support. All authors read the manuscript.
Financial assistance in the form of grants and fellowships from Indian Council of Medical Research (ICMR), Council of Scientific & Industrial Research (CSIR), Department of Biotechnology (DBT), and DST, government of India are gratefully acknowledged. BM is Emeritus Medical Scientist of ICMR and SY is CSIR research fellow.
Compliance with Ethical Standards
Conflict of interest
The authors declare no competing financial interests.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of SGPGIMS Lucknow and with the 1964 Helsinki declaration and its later amendments.
Informed consent was obtained from all individual participants included in the study.
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