Relationship between <i>UGT1A1</i> Polymorphisms and Adverse Effects of Irinotecan in Patients with Esophageal Carcinoma_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

XUEYang , ZENGFu-chun , SHUJun ,  CONGWei

Department of Thoracic Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, P. R. China;

Corresponding author：

CONGWei, Email: 1659815999@qq.com

Keywords：

Esophageal carcinoma; UDP glucuronosyltransferade 1 family, polypeptide A1; Gene polymorphism; Irinotecan; Diarrhea; Neutropenia

DOI：

10.7507/1007-4848.20140015

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Objective To investigate the distribution of uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms in esophageal carcinoma (EC) patients, and their relationship with adverse effects (delayed diarrhea and neutropenia) of Irinotecan. Methods Forty-eight patients with esophageal squamous carcinoma who were admitted to Sichuan Provincial People's Hospital between January and October 2012 were recruited in the study. There were 37 male and 11 female patients with their age of 56 (25-38) years. Formalin-fixed, paraffin-embedded samples were collected from those EC patients and genomic DNA was extracted. UGT1A1 polymorphisms were detected by PCR and DNA sequencing. Three genetic loci were investigated including UGT1A1^* 28 (TA6 > TA7), UGT1A1^* 6 (211G > A) and UGT1A1^* 93 (-3156G > A). Adverse effects (delayed diarrhea and neutropenia) of patients with different UGT1A1 polymorphisms after Irinotecan treatment were recorded. The relationship between UGT1A1 polymorphisms and Irinotecan-induced adverse effects was analyzed. Results UGT1A1 polymorphisms were detected in 10 out of 48 (20.8%) EC patients. UGT1A1^* 93 (-3156G > A)polymorphisms were most common with the polymorphism rate of 16.7% (8/48), followed by GT1A1^* 6 (211G > A) polymorphisms with the polymorphism rate of 4.2% (2/48). The incidences of grade 3~4 diarrhea and grade 3~4 neutropenia after Irinotecan treatment in the patients with UGT1A1 polymorphisms were 60.0% and 40.0% respectively, which were significantly higher than those of the patients with wild type UGT1A1 (21.1% and 15.8% respectively, P < 0.05). UGT1A1 polymorphism rates were 45.5% (5/11) in female patients and 13.5% (5/37) in male patients, which were significantly different (P < 0.05). Conclusions In EC patients, 2 polymorphism loci including UGT1A1^* 93 (-3156G > A) and GT1A1^* 6 (211G > A) can effectively predict adverse effects caused by Irinotecan treatment. UGT1A1 polymorphism rate of male patients is significantly lower than that of female patients.

Citation： XUEYang, ZENGFu-chun, SHUJun, CONGWei. Relationship between UGT1A1 Polymorphisms and Adverse Effects of Irinotecan in Patients with Esophageal Carcinoma. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2014, 21(1): 52-56. doi: 10.7507/1007-4848.20140015 Copy

1.	Gao Y, Hu N, Han X, et al.Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China.BMC cancer, 2009, 9:269.
2.	Innocenti F, Undevia SD, Iyer L, et al.Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.J Clin Oncol, 2004, 22 (8):1382-1388.
3.	Bhasker CR, McKinnon W, Stone A, et al.Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268:ethnic diversity of alleles and potential clinical significance.Pharmacogenetics, 2000, 10 (8):679-685.
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5.	Mackenzie PI, Bock KW, Burchell B, et al.Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily.Pharmacogenet Genomics, 2005, 15 (10):677-685.
6.	Iyer L, Janisch L, Das S, et al.UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11).Proc Am Soc Clin Oncol, 2001, 19:178A.
7.	Rosati G, Cordio S.Single-agent irinotecan as second-lined weekly chemotherapy in elderly patients with advanced colorectal cancer.Tumori, 2006, 92 (4):290-294.
8.	Cote JF, Kirzin S, Kramar A, et al.UGT1A1 polymorphism can predict hematologic toxicity in patients treated with Irinotecan.Clin Cancer Res, 2007, 13:3269-3275.
9.	王岩, 徐建明, 沈琳, 等.中国人尿苷二磷酸葡糖苷酸转移酶1A基因多态性与伊立替康毒性的相关性.中华肿瘤杂志, 2007, 29 (12):913-916.
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11.	Rhodes KE, Zhang W, Yang DY, et al.Abcb1, UGT1A1 and oatp-c polymorphisms predict Irinotecan (CPT-11) toxicity.J Clin Oncol, 2006, 24 (18 suppl):3074.
12.	Desai AA, Innocenti F, Ratain MJ.Pharmacogenomics:road to anti-cancer therapeutics nirvana? Ncogene, 2003, 22 (42):6621-6628.
13.	Han JY, Lim HS, Shin ES, et al.Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin.J Clin Oncol, 2006, 24 (15):2237-2244.
14.	Araki K, Fujita K, Ando Y, et al.A pharmacogenetic study of irinotecan:genetic polymorphisms in the coding region of UGT1A1 gene and SN-38 glucuronidation in the body.J Clin Oncol, 2006, 24 (18 suppl):13078.
15.	Han J, Lee S, Lee D, et al.Pharmacogenetic prediction for tumor response, toxicity, and survival of NSCLC patients treated with irinotecan and cisplatin chemotherapy.J Clin Oncol, 2007, 25 (18suppl):3581.
16.	Isobe H, Yamamoto N, Kunikane H, et al.A phase Ⅰ/Ⅱ, pharmacokinetic (PK) and pharmacogenomic (PG) study of weekly irinotecan (CPT-11) therapy for elderly patients with advanced non-small cell lung cancer.J Clin Oncol, 2007, 25 (18suppl):2539.
17.	Premawardhena A, Fisher CA, Liu YT, et al.The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1):hematologic and evolutionary implications.Blood Cells Mol Dis, 2003, 31 (1):98-101.
18.	Yong WP, Innocenti F, Ratain MJ.The role of pharmacogenetics in cancer therapeutics.Br J Clin Pharmacol, 2006, 62 (1):35-46.
19.	Innocenti F, Undevia SD, Iyer L, et al.Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.J Clin Oncol, 2004, 22 (8):1382-1388.
20.	Schulz C, Heinemann V, Schalhorn A, et al.UGT1A1 gene polymorphism:Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer.World J Gastroenterol, 2009, 15 (40):5058-5066.

1. Gao Y, Hu N, Han X, et al.Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China.BMC cancer, 2009, 9:269.
2. Innocenti F, Undevia SD, Iyer L, et al.Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.J Clin Oncol, 2004, 22 (8):1382-1388.
3. Bhasker CR, McKinnon W, Stone A, et al.Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268:ethnic diversity of alleles and potential clinical significance.Pharmacogenetics, 2000, 10 (8):679-685.
4. Hecht JR.Gastrointestinal toxicity or irinotecan.Oncology (Williston Park), 1998, 12 (8 Suppl 6):72-78.
5. Mackenzie PI, Bock KW, Burchell B, et al.Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily.Pharmacogenet Genomics, 2005, 15 (10):677-685.
6. Iyer L, Janisch L, Das S, et al.UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11).Proc Am Soc Clin Oncol, 2001, 19:178A.
7. Rosati G, Cordio S.Single-agent irinotecan as second-lined weekly chemotherapy in elderly patients with advanced colorectal cancer.Tumori, 2006, 92 (4):290-294.
8. Cote JF, Kirzin S, Kramar A, et al.UGT1A1 polymorphism can predict hematologic toxicity in patients treated with Irinotecan.Clin Cancer Res, 2007, 13:3269-3275.
9. 王岩, 徐建明, 沈琳, 等.中国人尿苷二磷酸葡糖苷酸转移酶1A基因多态性与伊立替康毒性的相关性.中华肿瘤杂志, 2007, 29 (12):913-916.
10. Jada SR, Lim R, Wong CI, et al.Role of UGT1A1^* 6, UGT1A1^* 28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.Cancer Sci, 2007, 98 (9):1461-1467.
11. Rhodes KE, Zhang W, Yang DY, et al.Abcb1, UGT1A1 and oatp-c polymorphisms predict Irinotecan (CPT-11) toxicity.J Clin Oncol, 2006, 24 (18 suppl):3074.
12. Desai AA, Innocenti F, Ratain MJ.Pharmacogenomics:road to anti-cancer therapeutics nirvana? Ncogene, 2003, 22 (42):6621-6628.
13. Han JY, Lim HS, Shin ES, et al.Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin.J Clin Oncol, 2006, 24 (15):2237-2244.
14. Araki K, Fujita K, Ando Y, et al.A pharmacogenetic study of irinotecan:genetic polymorphisms in the coding region of UGT1A1 gene and SN-38 glucuronidation in the body.J Clin Oncol, 2006, 24 (18 suppl):13078.
15. Han J, Lee S, Lee D, et al.Pharmacogenetic prediction for tumor response, toxicity, and survival of NSCLC patients treated with irinotecan and cisplatin chemotherapy.J Clin Oncol, 2007, 25 (18suppl):3581.
16. Isobe H, Yamamoto N, Kunikane H, et al.A phase Ⅰ/Ⅱ, pharmacokinetic (PK) and pharmacogenomic (PG) study of weekly irinotecan (CPT-11) therapy for elderly patients with advanced non-small cell lung cancer.J Clin Oncol, 2007, 25 (18suppl):2539.
17. Premawardhena A, Fisher CA, Liu YT, et al.The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1):hematologic and evolutionary implications.Blood Cells Mol Dis, 2003, 31 (1):98-101.
18. Yong WP, Innocenti F, Ratain MJ.The role of pharmacogenetics in cancer therapeutics.Br J Clin Pharmacol, 2006, 62 (1):35-46.
19. Innocenti F, Undevia SD, Iyer L, et al.Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.J Clin Oncol, 2004, 22 (8):1382-1388.
20. Schulz C, Heinemann V, Schalhorn A, et al.UGT1A1 gene polymorphism:Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer.World J Gastroenterol, 2009, 15 (40):5058-5066.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Relationship between UGT1A1 Polymorphisms and Adverse Effects of Irinotecan in Patients with Esophageal Carcinoma

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