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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Research article

The prognostic impact of GSTM1/GSTP1 genetic variants in bladder Cancer

Authors: Nada Albarakati, Dareen Khayyat, Asharf Dallol, Jaudah Al-Maghrabi, Taoufik Nedjadi

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

The glutathione S-transferases (GSTs) are a superfamily of phase II detoxifying enzymes that inactivates a wide variety of potential carcinogens through glutathione conjugation. Polymorphic changes in the GST genes have been reported to be associated with increased susceptibility to cancer development and anticancer drug resistance. In this study, we investigated the association between genetic variants in GSTM1 and GSTP1 and patients’ clinicopathological parameters. The prognostic values of such associations were evaluated among bladder cancer patients.

Methods

Genotyping of GSTM1 and GSTP1 in bladder cancer patients was assessed using polymerase chain reaction followed by DNA sequencing. Overall survival was estimated using the Kaplan-Meier method and multiple logistic regression and correlation analysis were performed.

Results

The GSTM1 null genotype was significantly associated with poor overall survival compared with the wild-type GSTM1 genotype. There was a trend towards better overall survival in patients with wild-type GSTP1 allele (AA) compared with GSTP1 (AG/GG) genotype. Interestingly, Kaplan-meier survival curve for GSTM1 null patients adjusted for sub-cohort with amplified HER2 gene showed poor survival compared with the GSTM1 null/ non-amplified HER2 gene. Also the same population when adjusted with HER2 protein expression, data showed poor survival for patients harboring GSTM1 null/high HER2 protein expression compared with low protein expression.

Conclusion

This study focuses on the impact of GSTM1 null genotype on bladder cancer patients’ outcome. Further investigations are required to delineate the underlying mechanisms of combined GSTM−/− and HER2 status in bladder cancer.
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Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.CrossRefPubMed
2.
Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nature Reviews Disease Primers. 2017;3:17022.PubMedCrossRef
3.
4.
Boada LD, Henríquez-Hernández LA, Navarro P, Zumbado M, Almeida-González M, Camacho M, et al. Exposure to polycyclic aromatic hydrocarbons (PAHs) and bladder cancer: evaluation from a gene-environment perspective in a hospital-based case-control study in the Canary Islands (Spain). Int J Occup Environ Health. 2015;21(1):23–30.PubMedPubMedCentralCrossRef
5.
Kellen E, Zeegers M, Paulussen A, Vlietinck R, Vlem EV, Veulemans H, et al. Does occupational exposure to PAHs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; the Belgian case control study on bladder cancer risk. Cancer Lett. 2007;245(1–2):51–60.PubMedCrossRef
6.
Ferrís J, Garcia J, Berbel O, Ortega JA. Constitutional and occupational risk factors associated with bladder cancer. Actas Urologicas Espanolas. 2013;37(8):513–22.PubMedPubMedCentral
7.
Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer. 2000;86(2):289–94.PubMedCrossRef
8.
Saint-Jacques N, Brown P, Nauta L, Boxall J, Parker L, Dummer TJB. Estimating the risk of bladder and kidney cancer from exposure to low-levels of arsenic in drinking water, Nova Scotia, Canada. Environ Int. 2018;110:95–104.PubMedCrossRef
9.
Glaser AP, Fantini D, Shilatifard A, Schaeffer EM, Meeks JJ. The evolving genomic landscape of urothelial carcinoma. Nature Rev Urol. 2017;14:215.CrossRef
10.
11.
Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione-S-transferase family of enzymes. Mutat Res. 2001;482(1–2):21–6.PubMedCrossRef
12.
13.
Sau A, Pellizzari Tregno F, Valentino F, Federici G, Caccuri AM. Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys. 2010;500(2):116–22.PubMedCrossRef
14.
Lin HJ, Han C-Y, Bernstein DA, Hsiao W, Lin BK, Hardy S. Ethnic distribution of the glutathione transferase mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibifity. Carcinogenesis. 1994;15(5):1077–81.PubMedCrossRef
15.
Benhamou S, Lee WJ, Alexandrie AK, Boffetta P, Bouchardy C, Butkiewicz D, et al. Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis. 2002;23(8):1343–50.PubMedCrossRef
16.
Ates NA, Tamer L, Ates C, Ercan B, Elipek T, Ocal K, et al. Glutathione S-transferase M1, T1, P1 genotypes and risk for development of colorectal cancer. Biochem Genet. 2005;43(3–4):149–63.PubMedCrossRef
17.
Singh M, Shah PP, Singh AP, Ruwali M, Mathur N, Pant MC, et al. Association of genetic polymorphisms in glutathione S-transferases and susceptibility to head and neck cancer. Mutat Res. 2008;638(1–2):184–94.PubMedCrossRef
18.
Yin X, Chen J. Is there any association between glutathione S-transferases M1 and glutathione S-transferases T1 Gene polymorphisms and endometrial Cancer risk? A Meta-analysis. Int J Prev Med. 2017;8:47.PubMedPubMedCentralCrossRef
19.
Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, et al. No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2006;15(5):1043–5.PubMedCrossRef
20.
Gorukmez O, Yakut T, Gorukmez O, Sag SO, Topak A, Sahinturk S, et al. Glutathione S-transferase T1, M1 and P1 genetic polymorphisms and susceptibility to colorectal Cancer in Turkey. Asian Pac J Cancer Prev. 2016;17(8):3855–9.PubMed
21.
Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS, Bae WK, et al. Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol. 2009;15(45):5716–21.PubMedPubMedCentralCrossRef
22.
Saint-Ruf C, Malfoy B, Scholl S, Zafrani B, Dutrillaux B. GST pi gene is frequently coamplified with INT2 and HSTF1 proto-oncogenes in human breast cancers. Oncogene. 1991;6(3):403–6.PubMed
23.
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
24.
Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM. The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in Cancer. Free Radic Biol Med. 2011;51(2):299–313.PubMedPubMedCentralCrossRef
25.
Zhang Y, Yuan Y, Chen Y, Wang Z, Li F, Zhao Q. Association between GSTP1 Ile105Val polymorphism and urinary system cancer risk: evidence from 51 studies. Onco Targets Ther. 2016;9:3565–9.PubMedPubMedCentral
26.
Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S. Association of genetic polymorphism of glutathione S-transferase (GSTM1, GSTT1, GSTP1) with bladder cancer susceptibility. Urol Oncol. 2013;31(7):1193–203.CrossRefPubMed
27.
Kellen E, Hemelt M, Broberg K, Golka K, Kristensen VN, Hung RJ, et al. Pooled analysis and meta-analysis of the glutathione S-transferase P1 Ile 105Val polymorphism and bladder cancer: a HuGE-GSEC review. Am J Epidemiol. 2007;165(11):1221–30.PubMedCrossRef
28.
Fontana L, Delort L, Joumard L, Rabiau N, Bosviel R, Satih S, et al. Genetic polymorphisms in CYP1A1, CYP1B1, COMT, GSTP1 and NAT2 genes and association with bladder cancer risk in a French cohort. Anticancer Res. 2009;29(5):1631–5.PubMed
29.
Yu Y, Li X, Liang C, Tang J, Qin Z, Wang C, et al. The relationship between GSTA1, GSTM1, GSTP1, and GSTT1 genetic polymorphisms and bladder cancer susceptibility: a meta-analysis. Medicine. 2016;95(37):e4900.PubMedPubMedCentralCrossRef
30.
Matic M, Pekmezovic T, Djukic T, Mimic-Oka J, Dragicevic D, Krivic B, et al. GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking-related bladder cancer: a case-control study. Urol Oncol. 2013;31(7):1184–92.PubMedCrossRef
31.
Meric-Bernstam F, Johnson AM, Dumbrava EEI, Raghav K, Balaji K, Bhatt M, et al. Advances in HER2-targeted therapy: novel agents and opportunities beyond breast and gastric Cancer. Clin Cancer Res. 2019;25(7):2033–41.PubMedCrossRef
32.
Tan TZ, Rouanne M, Tan KT, Huang RY, Thiery JP. Molecular subtypes of Urothelial bladder Cancer: results from a Meta-cohort analysis of 2411 tumors. Eur Urol. 2019;75(3):423–32.PubMedCrossRef
33.
Nedjadi T, Al-Maghrabi J, Assidi M, Dallol A, Al-Kattabi H, Chaudhary A, et al. Prognostic value of HER2 status in bladder transitional cell carcinoma revealed by both IHC and BDISH techniques. BMC Cancer. 2016;16:653.PubMedPubMedCentralCrossRef
34.
Akbani R, Ng PK, Werner HM, Shahmoradgoli M, Zhang F, Ju Z, et al. A pan-cancer proteomic perspective on the Cancer genome atlas. Nat Commun. 2014;5:3887.PubMedCrossRef
35.
36.
Zhao J, Xu W, Zhang Z, Song R, Zeng S, Sun Y, et al. Prognostic role of HER2 expression in bladder cancer: a systematic review and meta-analysis. Int Urol Nephrol. 2015;47(1):87–94.PubMedCrossRef
37.
Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.PubMedCrossRef
38.
Felsenstein KM, Theodorescu D. Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy. Nat Rev Urol. 2018;15(2):92–111.PubMedCrossRef
39.
Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41.PubMedCrossRef
40.
Lang M, Pelkonen O. Metabolism of xenobiotics and chemical carcinogenesis. IARC Sci Publ. 1999;148:13–22.
41.
Sawers L, Ferguson MJ, Ihrig BR, Young HC, Chakravarty P, Wolf CR, et al. Glutathione S-transferase P1 (GSTP1) directly influences platinum drug chemosensitivity in ovarian tumour cell lines. Br J Cancer. 2014;111(6):1150–8.PubMedPubMedCentralCrossRef
42.
Allocati N, Masulli M, Di Ilio C, Federici L. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis. 2018;7(1):8.PubMedPubMedCentralCrossRef
43.
Carless MA, Lea RA, Curran JE, Appleyard B, Gaffney P, Green A, et al. The GSTM1 null genotype confers an increased risk for solar keratosis development in an Australian Caucasian population. J Invest Dermatol. 2002;119(6):1373–8.PubMedCrossRef
44.
Kang HW, Song PH, Ha YS, Kim WT, Kim YJ, Yun SJ, et al. Glutathione S-transferase M1 and T1 polymorphisms: susceptibility and outcomes in muscle invasive bladder cancer patients. Eur J Cancer (Oxford, England: 1990). 2013;49(14):3010–9.CrossRef
45.
Yu C, Hequn C, Longfei L, Long W, Zhi C, Feng Z, et al. GSTM1 and GSTT1 polymorphisms are associated with increased bladder cancer risk: evidence from updated meta-analysis. Oncotarget. 2017;8(2):3246–58.PubMedCrossRef
46.
Srivastava DS, Mishra DK, Mandhani A, Mittal B, Kumar A, Mittal RD. Association of genetic polymorphism of glutathione S-transferase M1, T1, P1 and susceptibility to bladder cancer. Eur Urol. 2005;48(2):339–44.PubMedCrossRef
47.
Harries LW, Stubbins MJ, Forman D, Howard GC, Wolf CR. Identification of genetic polymorphisms at the glutathione S-transferase pi locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis. 1997;18(4):641–4.PubMedCrossRef
48.
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
49.
Ruano-Ravina A, Garcia-Basteiro AL, Perez-Rios M, Gomez-Mosquera A, Cerdeira-Carames S, Barros-Dios JM. Lung cancer survival and deletion of GSTM1 and GSTT1 genes. A case-series from Spain. Tumori. 2013;99(4):445–51.PubMedCrossRef
50.
Zhang J, Wu Y, Hu X, Wang B, Wang L, Zhang S, et al. GSTT1, GSTP1, and GSTM1 genetic variants are associated with survival in previously untreated metastatic breast cancer. Oncotarget. 2017;8(62):105905–14.PubMedPubMedCentral
51.
Anwar WA, Abdel-Rahman SZ, El-Zein RA, Mostafa HM, Au WW. Genetic polymorphism of GSTM1, CYP2E1 and CYP2D6 in Egyptian bladder cancer patients. Carcinogenesis. 1996;17(9):1923–9.PubMedCrossRef
52.
Katoh T, Inatomi H, Kim H, Yang M, Matsumoto T, Kawamoto T. Effects of glutathione S-transferase (GST) M1 and GSTT1 genotypes on urothelial cancer risk. Cancer Lett. 1998;132(1–2):147–52.PubMedCrossRef
53.
Srivastava DS, Kumar A, Mittal B, Mittal RD. Polymorphism of GSTM1 and GSTT1 genes in bladder cancer: a study from North India. Arch Toxicol. 2004;78(8):430–4.PubMedCrossRef
54.
Shao J, Gu M, Zhang Z, Xu Z, Hu Q, Qian L. Genetic variants of the cytochrome P450 and glutathione S-transferase associated with risk of bladder cancer in a south-eastern Chinese population. Int J Urol. 2008;15(3):216–21.PubMedCrossRef
55.
To-Figueras J, Gene M, Gomez-Catalan J, Galan C, Firvida J, Fuentes M, et al. Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1996;5(5):337–42.PubMed
56.
Ryk C, Berggren P, Kumar R, Hemminki K, Larsson P, Steineck G, et al. Influence of GSTM1, GSTT1, GSTP1 and NAT2 genotypes on the p53 mutational spectrum in bladder tumours. Int J Cancer. 2005;113(5):761–8.PubMedCrossRef
57.
Lo HW, Stephenson L, Cao X, Milas M, Pollock R, Ali-Osman F. Identification and functional characterization of the human glutathione S-transferase P1 gene as a novel transcriptional target of the p53 tumor suppressor gene. Mol Cancer Res. 2008;6(5):843–50.PubMedPubMedCentralCrossRef
58.
Grando JP, Kuasne H, Losi-Guembarovski R, Sant'ana Rodrigues I, Matsuda HM, Fuganti PE, et al. Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer. Clin Exp Med. 2009;9(1):21–8.PubMedCrossRef
Metadata
Title
The prognostic impact of GSTM1/GSTP1 genetic variants in bladder Cancer
Authors
Nada Albarakati
Dareen Khayyat
Asharf Dallol
Jaudah Al-Maghrabi
Taoufik Nedjadi
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6244-6

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