Association of TERT-CLPTM1L and 8q24 Common Genetic Variants with Gallbladder Cancer Susceptibility and Prognosis in North Indian Population
- 121 Downloads
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.
- Ahmadiyeh N, Pomerantz MM, Grisanzio C, Herman P, Jia L, Almendro V, He HH, Brown M, Liu XS, Davis M, Caswell JL, Beckwith CA, Hills A, Macconaill L, Coetzee GA, Regan MM, Freedman ML (2010) 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci USA 107(21):9742–9746CrossRefPubMedGoogle Scholar
- Banerjee R, Russo N, Liu M, Basrur V, Bellile E, Palanisamy N, Scanlon CS, van Tubergen E, Inglehart RC, Metwally T, Mani RS, Yocum A, Nyati MK, Castilho RM, Varambally S, Chinnaiyan AM, D’Silva NJ (2014) TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nat Commun 5:4527CrossRefPubMedPubMedCentralGoogle Scholar
- Ghoussaini M, Song H, Koessler T, Al Olama AA, Kote-Jarai Z, Driver KE, Pooley KA, Ramus SJ, Kjaer SK, Hogdall E, DiCioccio RA, Whittemore AS, Gayther SA, Giles GG, Guy M, Edwards SM, Morrison J, Donovan JL, Hamdy FC, Dearnaley DP, Ardern-Jones AT, Hall AL, O’Brien LT, Gehr-Swain BN, Wilkinson RA, Brown PM, Hopper JL, Neal DE, Pharoah PD, Ponder BA, Eeles RA, Easton DF, Dunning AM, U. K. G. P. C. S. C. B. A. o. U. S. S. o. Oncology and U. K. P. S. Collaborators (2008) Multiple loci with different cancer specificities within the 8q24 gene desert. J Natl Cancer Inst 100(13):962–966CrossRefPubMedPubMedCentralGoogle Scholar
- Jia J, Bosley AD, Thompson A, Hoskins JW, Cheuk A, Collins I, Parikh H, Xiao Z, Ylaya K, Dzyadyk M, Cozen W, Hernandez BY, Lynch CF, Loncarek J, Altekruse SF, Zhang L, Westlake CJ, Factor VM, Thorgeirsson S, Bamlet WR, Hewitt SM, Petersen GM, Andresson T, Amundadottir LT (2014) CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells. Cancer Res 74(10):2785–2795CrossRefPubMedPubMedCentralGoogle Scholar
- Kim T, Cui R, Jeon YJ, Lee JH, Lee JH, Sim H, Park JK, Fadda P, Tili E, Nakanishi H, Huh MI, Kim SH, Cho JH, Sung BH, Peng Y, Lee TJ, Luo Z, Sun HL, Wei H, Alder H, Oh JS, Shim KS, Ko SB, Croce CM (2014) Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5. Proc Natl Acad Sci USA 111(11):4173–4178CrossRefPubMedGoogle Scholar
- Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, Mirabello L, Jacobs K, Wheeler W, Yeager M, Bergen AW, Li Q, Consonni D, Pesatori AC, Wacholder S, Thun M, Diver R, Oken M, Virtamo J, Albanes D, Wang Z, Burdette L, Doheny KF, Pugh EW, Laurie C, Brennan P, Hung R, Gaborieau V, McKay JD, Lathrop M, McLaughlin J, Wang Y, Tsao MS, Spitz MR, Krokan H, Vatten L, Skorpen F, Arnesen E, Benhamou S, Bouchard C, Metspalu A, Vooder T, Nelis M, Valk K, Field JK, Chen C, Goodman G, Sulem P, Thorleifsson G, Rafnar T, Eisen T, Sauter W, Rosenberger A, Bickeboller H, Risch A, Chang-Claude J, Wichmann HE, Stefansson K, Houlston R, Amos CI, Fraumeni JF Jr, Savage SA, Bertazzi PA, Tucker MA, Chanock S, Caporaso NE (2009) A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 85(5):679–691CrossRefPubMedPubMedCentralGoogle Scholar
- Mhatre S, Wang Z, Nagrani R, Badwe R, Chiplunkar S, Mittal B, Yadav S, Zhang H, Chung CC, Patil P, Chanock S, Dikshit R, Chatterjee N, Rajaraman P (2017) Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol 18(4):535–544CrossRefPubMedGoogle Scholar
- Pintarelli G, Cotroneo CE, Noci S, Dugo M, Galvan A, Delli Carpini S, Citterio L, Manunta P, Incarbone M, Tosi D, Santambrogio L, Dragani TA, Colombo F (2017) Genetic susceptibility variants for lung cancer: replication study and assessment as expression quantitative trait loci. Sci Rep 7:42185CrossRefPubMedPubMedCentralGoogle Scholar
- Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, Jakobsdottir M, Helgadottir H, Thorlacius S, Aben KK, Blondal T, Thorgeirsson TE, Thorleifsson G, Kristjansson K, Thorisdottir K, Ragnarsson R, Sigurgeirsson B, Skuladottir H, Gudbjartsson T, Isaksson HJ, Einarsson GV, Benediktsdottir KR, Agnarsson BA, Olafsson K, Salvarsdottir A, Bjarnason H, Asgeirsdottir M, Kristinsson KT, Matthiasdottir S, Sveinsdottir SG, Polidoro S, Hoiom V, Botella-Estrada R, Hemminki K, Rudnai P, Bishop DT, Campagna M, Kellen E, Zeegers MP, de Verdier P, Ferrer A, Isla D, Vidal MJ, Andres R, Saez B, Juberias P, Banzo J, Navarrete S, Tres A, Kan D, Lindblom A, Gurzau E, Koppova K, de Vegt F, Schalken JA, van der Heijden HF, Smit HJ, Termeer RA, Oosterwijk E, van Hooij O, Nagore E, Porru S, Steineck G, Hansson J, Buntinx F, Catalona WJ, Matullo G, Vineis P, Kiltie AE, Mayordomo JI, Kumar R, Kiemeney LA, Frigge ML, Jonsson T, Saemundsson H, Barkardottir RB, Jonsson E, Jonsson S, Olafsson JH, Gulcher JR, Masson G, Gudbjartsson DF, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 41(2):221–227CrossRefPubMedPubMedCentralGoogle Scholar
- Troutman SM, Sissung TM, Cropp CD, Venzon DJ, Spencer SD, Adesunloye BA, Huang X, Karzai FH, Price DK, Figg WD (2012) Racial disparities in the association between variants on 8q24 and prostate cancer: a systematic review and meta-analysis. Oncologist 17(3):312–320CrossRefPubMedPubMedCentralGoogle Scholar
- Uchida N, Tsutsui K, Ezaki T, Fukuma H, Kobara H, Kamata H, Aritomo Y, Masaki T, Watanabe S, Kobayashi S, Nakatsu T, Nakano H, Kuriyama S (2003) Combination of assay of human telomerase reverse transcriptase mRNA and cytology using bile obtained by endoscopic transpapillary catheterization into the gallbladder for diagnosis of gallbladder carcinoma. Am J Gastroenterol 98(11):2415–2419CrossRefPubMedGoogle Scholar