SUMMARY. To determine the association of polymorphic variants of UGT1А1 (rs8175347), MTHFR (rs1801133), GSTP1 (rs1695) and ITPA (rs 1127354) with response to pla-tinum-based chemotherapy in patients with bladder cancer. The study group consisted of 60 patients who were treated at the National Cancer Institute. The population control groups were formed from conditionally healthy adults from different regions of Ukraine. Commercial DNA extraction kits were used to isolate genomic DNA of patients’ and controls’ blood samples. Genotyping for MTHFR, GSTP1 and ITPA alleles was performed using PCR followed by RFLP assay. Determination of allelic variants of UGT1А1 was carried out by fragment analysis of fluorescently labeled PCR products using an automatic laser analyzer ALF-express II. No significant difference was found in the distribution of allele and genotype frequencies of UGT1A1, MTHFR, GSTP1 and ITPA gene polymorphisms between the population samples and the study group of patients with bladder cancer. Similar to above, no statistically significant difference was found in the distribution of alleles and genotypes frequencies for the polymorphic loci of the UGT1A1, MTHFR and ITPA genes in codominant, dominant and recessive models between the groups of patients with bladder cancer who had a positive response to chemotherapy and those in whom the response for the therapy was absent. It was shown that in the group of patients who responded to chemotherapy, the frequency of the 313G allele of the GSTP1 gene (0.40) was statistically significantly higher than in the group of patients who did not respond to treatment (0.22). It was established that carriers of the 313G allele of the GSTP1 gene (AG and GG genotypes) have a higher probability of a positive response to chemotherapy than individuals with the AA genotype (OR = 3.05; CI 95 %:1.053–8.838). It has been shown that the A313G polymorphism of the GSTP1 gene (rs1695) is assosiated with the response to chemotherapy with platinum-based drugs, including Cisplatin. The presence of the 313G allele in the patient’s genotype may indicate a better sensitivity of the tumor to platinum-based drugs.
Keywords: bladder cancer, pharmacological markers, chemotherapy response, UGT1A1, MTHFR, GSTP1, ITPA
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Antoni, S., Ferlay, J., Soerjomataram, I., et al., Bladder cancer incidence and mortality: A global overview and recent trends, Eur. Urol., 2017, vol. 71, no. 1, pp. 96–108. https://doi.org/10.1016/j.eururo.2016.06.010
Barbarino, J.M., Haidar, C.E., Klein, T.E., and Altma, R.B., PharmGKB summary: very important pharmacogene information for UGT1A1, Pharmacogenet. Genomics, 2014, vol. 24, no. 3, pp. 177–183. https://doi.org/10.1097/FPC.0000000000000024
Cao, H. and Hegele, R.A., DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency, J. Hum. Genet., 2002, vol. 47, no. 11, pp. 620–622. https://doi.org/10.1007/s100380200095
Chen, H., Wang, X., and Gou, S., A cisplatin-based platinum (IV) prodrug containing a glutathione s-transferase inhibitor to reverse cisplatin-resistance in non-small cell lung cancer, J. Inorg. Biochem., 2019. https://doi.org/10.1016/j.jinorgbio.2019.01.014
Cheok, M.H. and Evans, W.E., Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy, Nat. Rev. Cancer, 2006, vol. 6, no. 2, pp. 117–129. https://doi.org/10.1038/nrc1800
Davis, R.J., Signal transduction by the JNK group of MAP kinases, Cell, 2000, vol. 103, no. 2, pp. 239–252. https://doi.org/10.1016/s0092-8674(00)00116-1
DeGeorge, K.C., Holt, H.R., and Hodges, S.C., Bladder cancer: diagnosis and treatment, Am. Fam. Physician, 2017, vol. 96, no. 8, pp. 507–514. https://www.aafp. org/pubs/afp/issues/2017/1015/p507.html.
Eisenhauer, E., Therasse, P., Bogaerts, J., et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eur. J. Cancer, 2009, vol. 45, no. 2, pp. 228–247. https://doi.org/10.1016/j.ejca.2008.10.026
Fernandez-Peralta, A.M., Daimiel, L., Nejda, N., et al., Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer. genetic and epigenetic characteristic of tumors and response to chemotherapy, Int. J. Colorectal Dis., 2010, vol. 25, no. 2, pp. 141–151. https://doi.org/10.1007/s00384-009-0779-y
Galsky, M.D., Sfakianos, J.P., and Ferket, B.S., Neoadjuvant chemotherapy in muscle-invasive bladder cancer: are things now getting personal?, Eur. Urol., 2017, vol. 72, no. 4, pp. 555–556. https://doi.org/10.1016/j.eururo.2017.04.012
Haiboniuk, I., Kravchenko, S., Makukh, H., et al., The frequency of associated with the Gilbert’s syndrome UGT1A1 gene low-functional allele 7(TA) (rs8175347) in Ukraine, Bull. Probl. Biol. Med., 2020, vol. 2, no. 156, pp. 91–96. https://doi.org/10.29254/2077-4214-2020-2-156-91-96
Han, B., Guo, Z., Ma, Y., et al., Association of GSTP1 and XRCC1 gene polymorphisms with clinical outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy, Int. J. Clin. Exp. Pathol., 2015, vol. 8, no. 4, pp. 4113–4119. PMCID: PMC4466987.
Harpole, D., Moore, M., Herndon, J.E., et al., The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer, Clin. Cancer Res., 2001, vol. 7, no. 3, pp. 562–569. https://aacrjournals.org/clincancerres/article/7/3/ 562/200075/The-Prognostic-Value-of-Molecular-Marker-Analysis.
Henderson, C., McLaren, A.W., Wolf, C.R., In vivo regulation of human glutathione transferase GSTP by chemopreventive agent, Cancer Res., 2014, vol. 74, no. 16, pp. 4378–4387. https://doi.org/10.1158/0008-5472.CAN-14-0792
Joerger, M., Burgers, S., Baas, P., et al., Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study, Cancer, 2012, vol. 118, no. 9, pp. 2466–2475. https://doi.org/10.1002/cncr.26562
Kaivosaari, S., Finel, M., and Kokinen, M., N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases, Xenobiotica, 2011, vol. 41, no. 8, pp. 652–669. https://doi.org/10.3109/00498254.2011.563327
Kang, H., Kim, W., and Yun, S., The therapeutic and prognostic implications of molecular biomarkers in urothelial carcinoma, Transl. Cancer Res., 2020, vol. 9, no. 10, pp. 6609–6623. https://doi.org/10.21037/tcr-20-1243
Kim, K.H., Lee, H.W., Ha, H.K., and Seo, H., Perioperative systemic therapy in muscle invasive bladder cancer: Current standard method, biomarkers and emerging strategies, Invest. Clin. Urol., 2023. https://doi.org/10.4111/icu.20230006
Kucherenko, A., Pampukha, V., Bobrova, I., et al., ITPA gene variant may protect against anemia induced during pegylated interferon alfa and ribavirin combination treatment in Ukrainian patients with chronic hepatitis, Tsitol. Genet., 2015, vol. 49, no. 12, pp. 38–41. https://core.ac.uk/reader/141666584?utm_source= linkout.
Moradveisi, B., Muwakkit, S., Zamani, F., et al., ITPA, TPMT and NUDT15 genetic polymorphisms predict 6-mercaptopurine toxicity in middle eastern children with acute lymphoblastic leukemia, Front. Pharmacol., 2019, vol. 10, p. 916. https://doi.org/10.3389/fphar.2019.00916
Niedersüss-Beke, D., Puntus, T., Kunit, T., et al., Neoadjuvant chemotherapy with gemcitabine plus cisplatin in patients with locally advanced bladder, Cancer Oncol., 2017, vol. 93, no. 1, pp. 36–42. https://doi.org/10.1159/000463389
Ogur, T., Fujiwara, Y., Katoh, O., et al., Glutathione S‑transferase-π gene expression and platinum drug exposure in human lung cancer, Cancer Lett., 2000, vol. 156, no. 1, pp. 93–99. https://doi.org/10.1016/s0304-3835(00)00447-x
Peklak-Scott, C., Smitherman, P.K., Townsend, A.J., and Morrow, C.S., Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin, Mol. Cancer Ther., 2008, vol. 7, no. 10, pp. 3247–3255. https://doi.org/10.1158/1535-7163.MCT-08-0250
Petrone, I., Bernardo, P.S., Dos Santos, E.C., and Abdelhay, E., MTHFR C677T and A1298C polymorphisms in breast cancer, gliomas and gastric cancer: A review, Genes (Basel), 2021, vol. 12, no. 4, p. 587. https://doi.org/10.3390/genes12040587
Ritchie, M.D., Hahn, L., and Moore, J.H., Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity, Genet. Epidemol., 2003, vol. 24, no. 2, pp. 150–57. https://doi.org/10.1002/gepi.10218
Sidaway, P., Bladder cancer: Targeted agents reverse chemotherapy resistance in urothelial carcinoma, Nat. Rev. Urol., 2016, vol. 13, no. 9, pp. 494–498. https://doi.org/10.1038/nrurol.2016.138
Singh, R.R. and Reindl, K.M., Glutathione S-Transferases in cancer, Antioxidants (Basel), 2021. https://doi.org/10.3390/antiox10050701
Ślusarczyk, A., Zapała, P., Zapała, Ł., Radziszewski, P., The impact of smoking on recurrence and progression of non-muscle invasive bladder cancer: a systematic review and meta-analysis, J. Cancer Res. Clin. Oncol., 2023. https://doi.org/10.1007/s00432-022-04464-6
Srougi, V., Gallucci, F.P., Mattedi, R.L., and Srougi, M., Carcinosarcoma of the bladder following local schistosomiasis infection, BMJ Case Rep., 2017. https://doi.org/10.1136/bcr-2016-218642
StatSoft, Inc. STATISTICA (Data Analysis Software System), Version 10, 2011. http://www.statsoft.com.
Sung, H., Ferlay, J., Siegel, R., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, Ca-Cancer J. Clin., 2021, vol. 71, no. 3, pp. 209–249. https://doi.org/10.3322/caac.21660
Tatarskyy, P.F., Kucherenko, A.M., Kravchenko, S.A., et al., Ischemic stroke in Ukrainian population: possible involvement of the F2 G20210A, F5 G1691A and MTHFR C677T gene variants, Biopolym. Cell, 2010, vol. 26, no. 4, pp. 299–305. http://biopolymers.org.ua/content/26/4/299/.
Tatarskyy, P.F., Chumachenko, N.G., Kucherenko, A.M., et al., Study of possible role of CYP1A1, GSTT1, GSTM1, GSTP, NAT2 and ADRB2 genes polymorphisms in bronchial asthma development in children, Biopolym. Cell, 2011, vol. 27, no. 1, pp. 66–73. http://www.biopolymers.org.ua/content/27/1/066/.
Towsend, D. and Tew, K.D., The role of glutathione-S-transferase in anti-cancer drug resistance, Oncogene, 2003, vol. 22, no. 47, pp. 7369–7375. https://doi.org/10.1038/sj.onc.1206940
Wan Rosalina, W.R., The, L.K., Mohamad, N., et al., Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine, J. Clin. Pharm. Ther., 2012, vol. 37, no. 2, pp. 237–241. https://doi.org/10.1111/j.1365-2710.2011.01272.x
Yang, L.-M., Li, X.-H., and Bao, C.-F., Glutathione S-transferase P1 and DNA polymorphisms influence response to chemotherapy and prognosis of bone tumors, Asian Pac. J. Cancer Prev., 2012, vol. 13, no. 11, pp. 5883–5886. https://doi.org/10.7314/apjcp.2012.13.11.5883
Yin, J.-Y., Huang, Q., Zhao, Y.-C., et al., Meta-analysis on pharmacogenetics of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients, PLoS One, 2012, vol. 7, no. 6, pp. 3–15. https://doi.org/10.1371/journal.pone.0038150