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UGT1A1*28 Polymorphism in Advanced Colorectal Cancer: The Story Is Not Yet Ended

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DOI: 10.4236/jct.2014.51007    3,559 Downloads   5,072 Views  


Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, while this study tried to investigate correlation with other toxicities like vomiting. Patients and Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, Group 1: patients with no mutation, Group 2: patients with homo or hetero mutation. All patients received standard IFL regimen. Primary objectives were: 1) comparison between the 2 groups as regard vomiting, 2) assessment of the incidence of UGT1A1*28 polymorphism. Secondary objectives were: comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS) and overall survival (OS). Results: 46 cases of advanced colorectal cancer present to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow-up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%), of whom 15% are homozygous. Grade (II-IV) vomiting was found in 8.3% of Group 1 versus 52.5% of Group 2 (P = 0.01). Grade (II-IV) neutropenia was found in 20.8% of Group 1 versus 64.7% of Group 2 (P = 0.03). Grade (II-IV) diarrhea was found in 37.5% of patients of Group 1 and 27.5% of patients with Group 2. (P = 0.75). Treatment delay occurred in 29.16% of Group 1 versus 72.4% of Group 2 (P = 0.02). 25% of Group 1 showed PD versus 25% of Group 2 (P = 0.8). 1-year PFS was 19% in Group 1 versus 23% in Group 2 (P = 0.8) while there was a trend towards better OS in Group 1 (47% versus 35%) (P = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.

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The authors declare no conflicts of interest.

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A. Bastawisy, A. Bahnasy, A. El-Zeiny and S. Farid, "UGT1A1*28 Polymorphism in Advanced Colorectal Cancer: The Story Is Not Yet Ended," Journal of Cancer Therapy, Vol. 5 No. 1, 2014, pp. 53-59. doi: 10.4236/jct.2014.51007.


[1] R. Siegel, D. Naishadham and A. Jemal, “Cancer Statistics,” CA: A Cancer Journal for Clinicians, Vol. 62, No. 1, 2012, pp. 10-29.
[2] G. G. Chabot, “Clinical Pharmacokinetics of Irinotecan,” Clinical Pharmacokinetics, Vol. 33, No. 4, 1997, pp. 245-259.
[3] J.-F. Cote, S. Kirzin, A. Kramar, J.-F. Mosnier, M.-D. Diebold, I. Soubeyran, A.-S. Thirouard, J. Selves, P. Laurent-Puig and M. Ychou, “UGT1A1 Polymorphism Can Predict Hematologic Toxicity,” Clinical Cancer Research, Vol. 13, 2007, p. 3269.
[4] L. Iyer, S. Das, L. Janisch, M. Wen, J. Rami’rez, T. Karrison, G. F. Fleming, E. E. Vokes, R. L. Schilsky and M. J. Ratain, “UGT1A1 Genotype and Irinotecan Disposition & Toxicity,” The Pharmacogenomics Journal, Vol. 2, 2002, pp. 43-47.
[5] L. Iyer, D. Hall, S. Das, M. A. Mortell, J. Ramirez, S. Kim, et al., “Phenotypegenotype Correlation of in Vitro SN-38 (Active Metabolite of Irinotecan) and Bilirubin Glucuronidation in Human Liver Tissue with UGT1A1 Promoter Polymorphism,” Clinical Pharmacology & Therapeutics, Vol. 65, 1999, pp. 576-582.
[6] F. Innocenti, C. Grimsley, S. Das, et al., “Haplotype Structure of the UDP-Glucuronosyltransferase 1A1 Promoter in Different Ethnic Groups,” Pharmacogenetics, Vol. 12, No. 9, 2002, pp. 725-733.
[7] H. Minami, K. Sai, M. Saeki, Y. Saito, S. Ozawa, K. Suzuki, N. Kaniwa, J. Sawada, T. Hamaguchi, N. Yamamoto, K. Shirao, Y. Yamada, H. Ohmatsu, K. Kubota, T. Yoshida, A. Ohtsu and N. Saijo, “Irinotecan Pharmacokinetics/Pharmacodynamics and UGT1A Genetic Polymorphisms in Japanese: Roles of UGT1A1*6 and *28,” Pharmacogenet Genomics, Vol. 17, No. 7, 2007, pp. 497-504.
[8] E. A. Eisenhauer, P. Therasse, B. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, et al., “New Response Evaluation Criteria in Solid Tumors: Revised RECIST Guideline (Version 1.1),” European Journal of Cancer, Vol. 45, No. 2, 2009, pp. 228-247.
[9] “Common Terminology Criteria for Adverse Events,” Version 4.0, DCTD, NCI, NIH, DHHS, 2009.
[10] L. Iyer1, S. Das, L. Janisch, M. Wen, J. Rami′rez, T. Karrison, G. F. Fleming, E. E. Vokes, R. L. Schilsky and M. J. Ratain, “UGT1A1*28 Polymorphism as a Determinant of Irinotecan Disposition and Toxicity,” The Pharmacogenomics Journal, Vol. 2, No. 1, 2002, pp. 43-47.
[11] Y. Akiyama, et al., “Genetic Testing for UGT1A1*28 and *6 in Japanese Patients Who Receive Irinotecan Chemotherapy,” Annals of Oncology, Vol. 19, No. 12, 2008, pp. 2089-2090.
[12] X. Q. Zhang, G. K. Ao, Y. W. Wang, W. Yan, M. Wang, E. F. Chen, F. F. Yang and J. Yang, “Genetic Variants and Haplotypes of the UGT1A9, 1A7 and 1A1 Genes in Chinese Han,” Genetics and Molecular Biology, Vol. 35, No. 2, 2012, pp. 428-434. 12005000036
[13] A. Zhang, Q. Xing, S. Qin, J. Du, L. Wang, L. Yu, X. Li, L. Xu, M. Xu, G. Feng, et al., “Intra-Ethnic Differences in Genetic Variants of the UGT-Glucuronosyltransferase 1A1 Gene in Chinese Populations,” Pharmacogenomics Journal, Vol. 7, No. 5, 2007, pp. 333-338. 1038/sj.tpj.6500424
[14] K. S. Tang, H. F. Chiu, H. H. Chen, H. L. Eng, C. J. Tsai, H. C. Teng and C. S. Huang, “Link between Colorectal Cancer and Polymorphisms in the Uridine-Diphosphoglucuronosyltransferase 1A7 and 1A1 Genes,” World Journal of Gastroenterology, Vol. 11, 2005, pp. 3250-3254.
[15] Y. Y. Zhou, L. Y. Lee, S. Y. Ng, C. P. P. Hia, K. T. Low, Y. S. Chong and D. L. M. Goh, “UGT1A1 Haplotype Mutation among Asians in Singapore,” Neonatology, Vol. 96, 2009, pp. 150-155.
[16] M. Saeki, Y. Saito, H. Jinno, K. Sai, S. Ozawa, K. Kurose, N. Kaniwa, K. Komamura, T. Kotake, H. Morishita, et al., “Haplotype Structures of the UGT1A Gene Complex in a Japanese Population,” Pharmacogenomics Journal, Vol. 6, 2006, pp. 63-75.
[17] S. S. Yea, S. S. Lee, W. Y. Kim, K. H. Liu, H. Kim, J. H. Shon, I. J. Cha and J. G. Shin, “Genetic Variations and Haplotypes of UDP-Glucuronosyltransferase 1A Locus in a Korean Population,” Therapeutic Drug Monitoring, Vol. 30, No. 1, 2008, pp. 23-34.
[18] S. S. Thomas, S. S. Li, J. W. Lampe, J. D. Potter and J. Bigler, “Genetic Variability, Haplotypes, and htSNPs for Exons 1 at the Human UGT1A Locus,” Human Mutation, Vol. 27, No. 7, 2006, p. e717.
[19] C. Schulz, V. Heinemann, A. Schalhorn, N. Moosmann, T. Zwingers, S. Boeck, C. Giessen and H.-J. Stemmler, “UGT1A1 Gene Polymorphism: Impact on Toxicity and Efficacy of Irinotecan-Based Regimens in Metastatic Colorectal Cancer,” World Journal of Gastroenterology, Vol. 15, No. 40, 2009, pp. 5058-5066.
[20] C.-Y. Liu, P.-M. Chen, T.-J. Chiou, J.-H. Liu, J. K. Lin, T.-C. Lin, W.-S. Chen, J.-K. Jiang, H.-S. Wang and W.-S. Wang, “UGT1A1*28 Polymorphism Predicts Irinotecan-Induced Severe Toxicities without Affecting Treatment Outcome and Survival in Patients with Metastatic Colorectal Carcinoma,” Cancer, Vol. 112, No. 9, 2008, pp. 1932-1940.
[21] K. K. Hahn, J. J. Wolff and J. M. Kolesar, “Pharmacogenetics and Irinotecan Therapy,” American Journal of Health-System Pharmacy, Vol. 63, No. 22, 2006, pp. 2211-2217. ajhp060155
[22] F. Innocenti, S. D. Undevia, L. Iyer, P. X. Chen, S. Das, M. Kocherginsky, T. Karrison, L. Janisch, J. Ramírez, C. M. Rudin, E. E. Vokes and M. J. Ratain, “Genetic Variants in the UDP-Glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan,” Journal of Clinical Oncology, Vol. 22, No. 8, 2004, pp. 1382-1388.
[23] E. Rouits, M. Boisdron-Celle, A. Dumont, O. Guérin, A. Morel and E. Gamelin, “Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity: A Molecular and Clinical Study of 75 Patients,” Clinical Cancer Research, Vol. 10, No. 15, 2004, pp. 5151-5159.
[24] G. E. Palomaki, L. A. Bradley, M. P. Douglas, K. Kolor and W. D. Dotson, “Can UGT1A1 Genotyping Reduce Morbidity and Mortality in Patients with Metastatic Colorectal Cancer Treated with Irinotecan? An Evidence-Based Review,” Genetics in Medicine, Vol. 11, No. 1, 2009, pp. 21-34.
[25] E. Marcuello, A. Altes, A. Menoyo, E. Del Rio, M. Gómez-Pardo and M. Baiget, “UGT1A1 Gene Variations and Irinotecan Treatment in Patients with Metastatic Colorectal Cancer,” British Journal of Cancer, Vol. 91, No. 4, 2004, pp. 678-682.
[26] G. Toffoli, E. Cecchin, G. Corona, et al., “The Role of UGT1A1*28 Polymorphism in the Pharmacodynamics and Pharmacokinetics of Irinotecan in Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 24, No. 19, 2006, pp. 3061-3068. 1200/JCO.2005.05.5400

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