Published: 2018-08-23

Ethnic differences in allele, genotype distributions and lung cancer risk of polymorphisms of gemcitabine metabolic pathway genes in south Indian population

Devika Tirumalasetty, Deepak Gopal Shewade, Biswajit Dubashi, Srinivasa Rao Katiboina


Background: Gemcitabine is a widely used cytotoxic drug in the treatment of a number of solid tumors, for instance, lung, pancreatic as well as breast cancer. As a consequence of the progressive genomic instability, the efficiency rates have eventually lowered. Genetic approach targeting one or several genes in drug targeting pathways facilitates substantially more valuable details in explaining the association between variants and also the efficacy of gemcitabine therapy. In addition, several researchers have reported ethnic discrepancies in clinical response to gemcitabine. Thus, the present study was aimed to establish the normative frequencies of genes associated with the metabolic pathway of Gemcitabine (RRM1 -37C>A (rs12806698), RRM1 -524T>C (rs11030918), CDA 79A>C (rs2072671) and CDA 435 C>T (rs1048977) in South Indian healthy population and compared with 1000 genome population. Additionally, the association of these SNPs with the risk of developing lung cancer was also evaluated.

Methods: This study was carried out on 184 healthy subjects and 123 lung cancer patients of South Indian origin and genotyping was done using RT-PCR (Real Time Polymerase Chain Reaction). The frequencies of the above polymorphisms were in Hardy-Weinberg equilibrium (p >0 .05).

Results: The minor allele frequencies of the SNPs RRM1 -37C>A (rs12806698), RRM1 -524T>C (rs11030918), CDA 79A>C (rs2072671) and CDA -435 C>T (rs1048977) were 31.3, 36.7, 24.5 and 22.0 respectively.

Conclusions: There was a significant difference observed between the genotype and allele frequencies of south Indians with the 1000 genome populations. We also found that SNPs of RRM1 were significantly associated with lung cancer risk.


CDA, Ethnic, Gemcitabine, Lung cancer risk, Polymorphisms, RRM1

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Union for International Cancer Control. Agency for Research on Cancer. Globocan; 2008. Fast Stats. Available at: [Last accessed on 2018 August 3]

Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology Treatment of Unresectable Non–Small-Cell Lung Cancer Guideline: Update 2003. J Clin Oncol. 2004;22(2):330-53.

Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F. Role of gemcitabine in cancer therapy. Future Oncol Lond Engl. 2005;1(1):7-17.

Metro G, Cappuzzo F, Finocchiaro G, Toschi L, Crinò L. Development of gemcitabine in non-small cell lung cancer: the Italian contribution. Ann Oncol Off J Eur Soc Med Oncol. 2006;17 Suppl 5:v37-46.

Zhang L, Gao G, Li X, Ren S, Li A, Xu J, et al. Association between Single Nucleotide Polymorphisms (SNPs) and Toxicity of Advanced Non-Small-Cell Lung Cancer Patients Treated with Chemotherapy. Perez-Gracia JL, editor. PLoS ONE. 2012;7(10):e48350.

Burke W, Khoury MJ, Stewart A, Zimmern RL. The path from genome-based research to population health: development of an international public health genomics network. Genet Med. 2006;8(7):451-8.

Ma Q, Lu AYH. Pharmacogenetics, Pharmacogenomics, and Individualized Medicine. Pharmacol Rev. 2011;63(2):437-59.

Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996;23(5 Suppl 10):3-15.

Joerger M, Burgers JA, Baas P, Doodeman VD, Smits PHM, Jansen RS, et al. Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non-small-cell lung cancer patients receiving cisplatin/gemcitabine. Cancer Chemother Pharmacol. 2011;69(1):25-33.

Tibaldi C, Giovannetti E, Tiseo M, Leon LG, D’Incecco A, Loosekoot N, et al. Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients. Ann Oncol. 2011;23(3):670-7.

Soo RA, Wang LZ, Ng SS, Chong PY, Yong WP, Lee SC, et al. Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients. Lung Cancer. 2009;63(1):121-7.

Gong W, Zhang X, Wu J, Chen L, Li L, Sun J, et al. RRM1 expression and clinical outcome of gemcitabine-containing chemotherapy for advanced non-small-cell lung cancer: A meta-analysis. Lung Cancer. 2012;75(3):374-80.

Bepler G, Zheng Z, Gautam A, Sharma S, Cantor A, Sharma A, et al. Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance. Lung Cancer. 2005;47(2):183-92.

West H, Lilenbaum R, Harpole D, Wozniak A, Sequist L. Molecular analysis-based treatment strategies for the management of non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2009;4(9 Suppl 2):S1029-1039-1042.

Obasaju CK, Ansari RH, Socinski MA, Chen R, Monberg MJ, Catalano RB, et al. A Comparison of white and African American outcomes from a three-arm, randomized, phase III multicenter trial of advanced or metastatic non-small cell lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2010;5(7):993-1000.

O’Donnell PH, Dolan ME. Cancer Pharmacoethnicity: Ethnic Differences in Susceptibility to the Effects of Chemotherapy. Clin Cancer Res. 2009;15(15):4806-14.

Tamang R, Singh L, Thangaraj K. Complex genetic origin of Indian populations and its implications. J Biosci. 2012;37(5):911-9.

Soo RA, Kawaguchi T, Loh M, Ou SHI, Shieh MP, Cho BC, et al. Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol. 2012;8(4):451-62.

Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K, et al. Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism. J Clin Oncol. 2006;25(1):32-42.

Tanaka M, Javle M, Dong X, Eng C, Abbruzzese JL, Li D. Gemcitabine Metabolic and Transporter Gene Polymorphisms Are Associated with Drug Toxicity and Efficacy in Patients with Locally Advanced Pancreatic Cancer. Cancer. 2010;116(22):5325-35.

Soo RA, Wang LZ, Ng SS, Chong PY, Yong WP, Lee SC, et al. Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients. Lung Cancer. 2009;63(1):121-7.

Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 2006;17(12):1818-25.

Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, et al. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(4):1318-25.

Boukovinas I, Papadaki C, Mendez P, Taron M, Mavroudis D, Koutsopoulos A, et al. Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients. PLOS ONE. 2008;3(11):e3695.

Rha SY, Jeung HC, Choi YH, Yang WI, Yoo JH, Kim BS, et al. An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. The Oncologist. 2007;12(6):622-30.

Dong S, Guo AL, Chen ZH, Wang Z, Zhang XC, Huang Y, et al. RRM1 single nucleotide polymorphism-37C→ A correlates with progression-free survival in NSCLC patients after gemcitabine-based chemotherapy. J Hematol Oncol J Hematol Oncol. 2010;3(1):10.

Kim SO, Jeong JY, Kim MR, Cho HJ, Ju JY, Kwon YS, et al. Efficacy of Gemcitabine in Patients with Non-Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene. Clin Cancer Res. 2008;14(10):3083-8.

Xu XL, Zheng J, Mao WM, Ling ZQ. RRM1 *151Aandgt;T, RRM1 -756Tandgt;C, and RRM1 -585Tandgt;Gis associated with increased susceptibility of lung cancer in Chinese patients. Cancer Med. 2016;5(8):2084-90.

Coskunpinar E, Yildiz P, Aynaci E, Turna A, Musteri Oltulu Y, Hekimoglu E, et al. Investigation of some DNA repair genes association in non small cell lung cancer. Cell Mol Biol. 2015;61(8):57-62.

Li X, Zhang J, Su C, Zhao X, Tang L, Zhou C. The association between polymorphisms in the DNA nucleotide excision repair genes and RRM1 gene and lung cancer risk. Thorac Cancer. 2012;3(3):239-48.

Zhang GB, Chen J, Wang LR, Li J, Li MW, Xu N, et al. RRM1 and ERCC1 expression in peripheral blood versus tumor tissue in gemcitabine/carboplatin-treated advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;69(5):1277-87.

Ulker M, Duman BB, Sahin B, Gumurdulu D. ERCC1 and RRM1 as a predictive parameter for non-small cell lung, ovarian or pancreas cancer treated with cisplatin and/or gemcitabine. Contemp Oncol (Pozn). 2015;3:207-13.

Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M, et al. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res Off J Am Assoc Cancer Res. 2004 ;10:4215s-4219s.

Dumontet C, Morschhauser F, Solal-Celigny P, Bouafia F, Bourgeois E, Thieblemont C, et al. Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma. Br J Haematol. 2001;113(3):772-8.

McDonagh EM, Whirl-Carrillo M, Garten Y, Altman RB, Klein TE. From pharmacogenomic knowledge acquisition to clinical applications: the PharmGKB as a clinical pharmacogenomic biomarker resource. Biomark Med. 2011;5(6):795-806.

Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol Off J Eur Soc Med Oncol. 2006;17 Suppl 5:v7-12.

Rosell R, Cobo M, Isla D, Camps C, Massuti B. Pharmacogenomics and gemcitabine. Ann Oncol. 2006;17(5):v13-6.

Zhou M, Wan HY, Gao BL, Ding YJ, Jun RX. Genetic polymorphisms of XPD and CDA and lung cancer risk. Oncol Lett. 2012;4(2):247-51.

Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, et al. Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin-Treated Advanced Non-Small Cell Lung Cancer Patients. Clin Cancer Res. 2008;14(6):1797-803.

Li H, Wang X, Wang X. The impact of CDA A79C gene polymorphisms on the response and hematologic toxicity in gemcitabine-treated patients: A meta-analysis. Int J Biol Markers. 2014;29(3):224-32.

Mitra AK, Kirstein MN, Khatri A, Skubitz KM, Dudek AZ, Greeno EW, et al. Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors. Pharmacogenomics. 2012;13(9):1009-21.

Fukunaga AK, Marsh S, Murry DJ, Hurley TD, McLeod HL. Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenomics J. 2004;4(5):307-14.

Sugiyama E, Lee SJ, Lee SS, Kim WY, Kim SR, Tohkin M, et al. Ethnic differences of two non-synonymous single nucleotide polymorphisms in CDA gene. Drug Metab Pharmacokinet. 2009;24(6):553-6.

Xu J, Zhou Y, Zhang J, Chen Y, Zhuang R, Liu T, et al. High incidence of severe neutropenia after gemcitabine-based chemotherapy in Chinese cancer patients with CDA 79A>C mutation. Clin Chim Acta. 2012;413(15-16):1284-7.

Iyer SN, Ankala A, Singhal RS, Hegde MR. Determination of common genetic variants in cytidine deaminase (CDA) gene in Indian ethnic population. Gene. 2013;524(1):35-9.

Ding X, Chen W, Fan H, Zhu B. Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy. Gene. 2015;559(1):31-7.