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Molecular Diagnosis & Therapy

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01-12-2013 | Original Research Article

Pharmacogenetic Influence of GST Polymorphisms on Anthracycline-Based Chemotherapy Responses and Toxicity in Breast Cancer Patients: A Multi-Analytical Approach

Authors: Sonam Tulsyan, Pankaj Chaturvedi, Gaurav Agarwal, Punita Lal, Sushma Agrawal, Rama Devi Mittal, Balraj Mittal

Published in: Molecular Diagnosis & Therapy | Issue 6/2013

Abstract

Background and Objective

Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione-S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients.

Method

Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile¹⁰⁵Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene–gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis.

Results

In single-locus analysis, Ile/Val and Ile/Val + Val/Val genotypes of the GSTP1 Ile¹⁰⁵Val (rs1695) polymorphism reached statistical significance with grade 2–4 anemia (P = 0.019, P = 0.027). On performing gene–gene interaction analysis, GSTM1 null-GSTP1 Ile/Val was significantly associated with response to NACT (P = 0.032). On evaluating higher order gene–gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile¹⁰⁵Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile¹⁰⁵Val showed significant association with treatment response, grade 2–4 anemia, and dose delay/reduction due to neutropenia (P = 0.046, P = 0.027, P = 0.026), respectively.

Conclusion

Multi-analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes.

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Rodrigues FF, Santos RE, Melo MB, Silva MA, Oliveira AL, Rozenowicz RL, et al. Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer. Genet Mol Res. 2008;7(1):177–83.PubMedCrossRef

Arun BK, Granville LA, Yin G, Middleton LP, Dawood S, Kau SW, et al. Glutathione-S-transferase-pi expression in early breast cancer: association with outcome and response to chemotherapy. Cancer Invest. 2010;28(5):554–9.PubMedCrossRef

Huang MY, Wang YH, Chen FM, Lee SC, Fang WY, Cheng TL, et al. Multiple genetic polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan. Ann Surg Oncol. 2008;15(3):872–80.PubMedCrossRef

Hirshfield KM, Rebbeck TR, Levine AJ. Germline mutations and polymorphisms in the origins of cancers in women. J Oncol. 2010. 297671. doi:10.1155/2010/297671.

Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47):7369–75.PubMedCrossRef

Armstrong RN. Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol. 1997;10(1):2–18.PubMedCrossRef

Zhong S, Huang M, Yang X, Liang L, Wang Y, Romkes M, et al. Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol. 2006;62(4):457–72.PubMedCrossRef

Perry RR, Mazetta JA, Levin M, Barranco SC. Glutathione levels and variability in breast tumors and normal tissue. Cancer. 1993;72(3):783–7.PubMedCrossRef

Williams JA, Phillips DH. Mammary expression of xenobiotic metabolizing enzymes and their potential role in breast cancer. Cancer Res. 2000;60(17):4667–77.PubMed

10.

Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, et al. Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem. 2001;276(16):12749–55.PubMedCrossRef

11.

Chaturvedi P, Tulsyan S, Agarwal G, Lal P, Agarwal S, Mittal RD, et al. Influence of ABCB1 genetic variants in breast cancer treatment outcomes. Cancer Epidemiol. 2013. doi:10.1016/j.canep.2013.04.012.PubMed

12.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.PubMedCrossRef

13.

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.PubMedCrossRef

14.

Toruner GA, Akyerli C, Ucar A, Aki T, Atsu N, Ozen H, et al. Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and bladder cancer susceptibility in the Turkish population. Arch Toxicol. 2001;75(8):459–64.PubMedCrossRef

15.

Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J. Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem. 1997;272(15):10004–12.PubMedCrossRef

16.

Gauderman WJ. Sample size requirements for matched case-control studies of gene–environment interaction. Stat Med. 2002;21(1):35–50.PubMedCrossRef

17.

Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene–gene and gene-environment interactions. Bioinformatics. 2003;19(3):376–82.PubMedCrossRef

18.

Ballet F, Robert J, Bouma ME, Vrignaud P, Infante R. Metabolism of doxorubicin and epirubicin in adult human hepatocytes in culture. Pharmacol Res Commun. 1986;18(4):343–7.PubMedCrossRef

19.

Camaggi CM, Strocchi E, Comparsi R, Testoni F, Angelelli B, Pannuti F. Biliary excretion and pharmacokinetics of 4’epidoxorubicin (epirubicin) in advanced cancer patients. Cancer Chemother Pharmacol. 1986;18(1):47–50.PubMedCrossRef

20.

Coffman BL, King CD, Rios GR, Tephly TR. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos. 1998;26(1):73–7.PubMed

21.

Khedhaier A, Remadi S, Corbex M, Ahmed SB, Bouaouina N, Mestiri S, et al. Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma. Br J Cancer. 2003;89(8):1502–7. doi:10.1038/sj.bjc.66012926601292.PubMedCrossRef

22.

Mishra A, Chandra R, Mehrotra PK, Bajpai P, Agrawal D. Glutathione S-transferase M1 and T1 polymorphism and response to neoadjuvant chemotherapy (CAF) in breast cancer patients. Surg Today. 2011;41(4):471–6. doi:10.1007/s00595-009-4310-4.PubMedCrossRef

23.

Zhang BL, Sun T, Zhang BN, Zheng S, Lu N, Xu BH, et al. Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer. Chin Med J (Engl). 2011;124(2):199–204.PubMed

24.

Yang G, Shu XO, Ruan ZX, Cai QY, Jin F, Gao YT, et al. Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer. 2005;103(1):52–8. doi:10.1002/cncr.20729.PubMedCrossRef

25.

Yao S, Barlow WE, Albain KS, Choi JY, Zhao H, Livingston RB, et al. Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. Clin Cancer Res. 2010;16(24):6169–76. doi:10.1158/1078-0432.CCR-10-0281.PubMedCrossRef

26.

Lizard-Nacol S, Coudert B, Colosetti P, Riedinger JM, Fargeot P, Brunet-Lecomte P. Glutathione S-transferase M1 null genotype: lack of association with tumour characteristics and survival in advanced breast cancer. Breast Cancer Res. 1999;1(1):81–7. doi:10.1186/bcr17.PubMedCrossRef

27.

Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW, et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol. 2009;27(33):5519–28. doi:10.1200/JCO.2008.21.6283.PubMedCrossRef

28.

Huang J, Tan PH, Thiyagarajan J, Bay BH. Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. Mod Pathol. 2003;16(6):558–65.PubMedCrossRef

29.

Harpole DH Jr, Moore MB, Herndon JE 2nd, Aloia T, D’Amico TA, Sporn T, et al. The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res. 2001;7(3):562–9.PubMed

30.

Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S, et al. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res. 1998;4(6):1469–74.PubMed

31.

Yokoyama Y, Sato S, Fukushi Y, Sakamoto T, Futagami M, Saito Y. Significance of multi-drug-resistant proteins in predicting chemotherapy response and prognosis in epithelial ovarian cancer. J Obstet Gynaecol Res. 1999;25(6):387–94.PubMedCrossRef

32.

Shiga H, Heath EI, Rasmussen AA, Trock B, Johnston PG, Forastiere AA, et al. Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. Clin Cancer Res. 1999;5(12):4097–104.PubMed

33.

Hamajima N, Takezaki T, Tajima K. Allele frequencies of 25 polymorphisms pertaining to cancer risk for Japanese, Koreans and Chinese. Asian Pac J Cancer Prev. 2002;3(3):197–206.PubMed

Title: Pharmacogenetic Influence of GST Polymorphisms on Anthracycline-Based Chemotherapy Responses and Toxicity in Breast Cancer Patients: A Multi-Analytical Approach
Authors: Sonam Tulsyan
Pankaj Chaturvedi
Gaurav Agarwal
Punita Lal
Sushma Agrawal
Rama Devi Mittal
Balraj Mittal
Publication date: 01-12-2013
Publisher: Springer International Publishing
Published in: Molecular Diagnosis & Therapy / Issue 6/2013
Print ISSN: 1177-1062
Electronic ISSN: 1179-2000
DOI: https://doi.org/10.1007/s40291-013-0045-4

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Abstract

Background and Objective

Method

Results

Conclusion

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