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 ...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.展开更多
Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of i...Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.展开更多
This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates...This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group（case group, n=108） and healthy neonates group（control group, n=60）. Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1＊28 and Gly71 Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that：（1） The frequency of UGT1A1＊28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups（P〉0.05）.（2） The frequency of Gly71 Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups（P〈0.01）.（3） The serum bilirubin level of Gly71 Arg mutant homozygous and heterozygous subgroups（n=66） in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup（n=42）（P〈0.01）. It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1＊28 gene polymorphism, but closely with the Gly71 Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.展开更多
AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan. METHODS: We enrolled 50 healthy volunteers from ...AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan. METHODS: We enrolled 50 healthy volunteers from each of the Yamaguchi (western part of Japan), Kochi(southern part of Japan) and Akita (northern part of Japan) prefectures. Blood samples (7 mL) were collected from each participant and stored in EDTA for subsequent genotyping by fragment size analysis, direct sequencing and TaqMan assay of UGT1A1*28, UGT1A7*3/UGT1A9*22 and UGT1A1*93/UGT1A1*6/ UGT1A1*27/UGT1A1*60/UGT1A7 (-57), respectively. RESULTS: The only statistically significant differences in allele polymorphisms among the group examined were for UGT1A1*6. The Akita population showed more UGT1A1*6 heterozygosity (P = 0.0496). CONCLUSION: Our study revealed no regional diversity among UGT1A1, UGT1A7 or UGT1A9 polymorphisms in Japan.展开更多
Objective： Hepatocellular carcinoma （HCC） is a complex disease which associates with both environmental and genetic factors. The purpose of this study was to investigate whether the genetic polymorphisms of UDP-glu...Objective： Hepatocellular carcinoma （HCC） is a complex disease which associates with both environmental and genetic factors. The purpose of this study was to investigate whether the genetic polymorphisms of UDP-glucuronosyltransferase（UGT1A7）, an important phase II biotransformation enzyme, and X-ray repair cross-complementing group 1（XRCC1）, a pivotal DNA-repair gene, were related to the risk of HCC in Northeast China. Methods： One hundred and thirty six HCC patients and one hundred and thirty six frequency-matched controls were included in this hospital-based case-control study. Genotypes of UGT1A7 and XRCC1 were determined using allele-specific polymerase chain reaction （AS-PCR） and PCR-restriction fragment length polymorphism （RFLP）, and for which the odds ratio （OR） with 95% confidence interval （95% CI） were calculated. Results： The proportion of UGT1A7 low enzymatic allele （＊2 or ＊3） was higher in HCC patients than those in controls. The UGT1A7＊1/＊2 and ＊3/＊3 genotypes were associated with higher HCC risk （OR=2.09, 95%CI： 1.10-3.97; OR=5.67, 95%CI： 1.76-18.30, respectively）. The XRCC1 codon 399 Arg/Gln genotype could also elevate HCC risk （OR=2.16, 95% CI 1.29-3.61）. In addition to polymorphisms of UGT1A7 and XRCC1, multivariate logistic regression analysis demonstrated that other significant independent factors associated with HCC were HBV infection （OR=68.07, 95%CI： 28.03-165.26）, HCV infection （OR=30.97, 95%CI： 8.06-118.94） and family history of HCC （OR=10.62, 95%CI： 2.22-50.77）. Conclusion： The study shows that the polymorphisms of UGT1A7 and XRCC1 are associated with HCC risk. Determination of the polymorphisms of UGT1A7 and XRCC1 may provide an important clue to preventive measure against HCC.展开更多
AIM: Single nucleotide polymorphisms (SNPs) of uridinediphosphoglucuro -nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. W...AIM: Single nucleotide polymorphisms (SNPs) of uridinediphosphoglucuro -nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. We performed this research to establish the techniques for determining UGT1A7 gene and basic data of this gene for Taiwan Chinese. METHODS: We collected blood samples from 112 healthy adults and 505 subjects carrying different genotypes of UGT1A1, and determined the promoter area and the entire sequence of UGT1A7 exon 1 by polymerase chain reaction. We designed appropriate primers and restriction enzymes to detect variant UGT1A7 genotypes found in the study subjects. RESULTS: Six SNPs at nucleotides 33, 387, 391, 392, 622, and 756 within the coding region of UGT1A7 exon 1 were found. The incidence of UGT1A7*l/*2 (N129R131W208/ K129K131W208) was predominant (35.7%) while that of UGT1A7 *3/*3 (K129K131R208/K129K131R208) was the least (2.7%). The allele frequency of UGT1A7*3, which exists in a considerable proportion of Caucasians (0.361) and Japanese (0.255), was identified only to be 0.152 in our study subjects. A novel variation at nucleotide -57 in the upstream was found, which was associated with SNPs at nucleotides 33, 387, 391, 392, and 622 in one of the variant haplotypes. The nucleotide changes at positions 387, 391, 392 and 756 were in linkage in another variant haplotype. The allele frequency of UGT1A7*3 was 0.018, 0.158, 0.242, 0.433, and 0.920 in subjects carrying wild, A(TA)6TAA/A(TA)7TAA, A(TA)7TAA/A(TA)7TAA, 211G/211A, and 211A/211A variants of UGT1A1 gene, respectively. By using natural or mutagenesis primers, we successfully detected the variations at nucleotides -57, 33, 387, and 622 with the restriction enzymes HpyCH4 Ⅳ, TaqⅠ, AflⅡ, and Rsa Ⅰ, respectively. CONCLUSION: The results indicate that the allele frequencies of UGT1A7 gene in Taiwan Chinese are different from those in Caucasians and Japanese. Carriage of the nucleotide 211- variant UGT1A gene is highly associated with UGT1A7*3. The restriction-enzymedigestion method for the determination of nucleotides-57 (or 33, or 622) and 387 can rapidly identify genotypes of UGT1A7 in an individual.展开更多
文摘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.
基金Supported by National Natural Science Foundation Project,Grants No.30971579Capital Development Foundation,No.2007-2029
文摘Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.
基金supported by the National Natural Science Foundation of China(No.81370099)
文摘This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group（case group, n=108） and healthy neonates group（control group, n=60）. Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1＊28 and Gly71 Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that：（1） The frequency of UGT1A1＊28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups（P〉0.05）.（2） The frequency of Gly71 Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups（P〈0.01）.（3） The serum bilirubin level of Gly71 Arg mutant homozygous and heterozygous subgroups（n=66） in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup（n=42）（P〈0.01）. It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1＊28 gene polymorphism, but closely with the Gly71 Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.
基金Supported by The Non-profit Epidemiological and Clinical Research Information Network Organization
文摘AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan. METHODS: We enrolled 50 healthy volunteers from each of the Yamaguchi (western part of Japan), Kochi(southern part of Japan) and Akita (northern part of Japan) prefectures. Blood samples (7 mL) were collected from each participant and stored in EDTA for subsequent genotyping by fragment size analysis, direct sequencing and TaqMan assay of UGT1A1*28, UGT1A7*3/UGT1A9*22 and UGT1A1*93/UGT1A1*6/ UGT1A1*27/UGT1A1*60/UGT1A7 (-57), respectively. RESULTS: The only statistically significant differences in allele polymorphisms among the group examined were for UGT1A1*6. The Akita population showed more UGT1A1*6 heterozygosity (P = 0.0496). CONCLUSION: Our study revealed no regional diversity among UGT1A1, UGT1A7 or UGT1A9 polymorphisms in Japan.
基金supported by the grant from Department of Education of Liaoning Province, China (No. 2008S232)
文摘Objective： Hepatocellular carcinoma （HCC） is a complex disease which associates with both environmental and genetic factors. The purpose of this study was to investigate whether the genetic polymorphisms of UDP-glucuronosyltransferase（UGT1A7）, an important phase II biotransformation enzyme, and X-ray repair cross-complementing group 1（XRCC1）, a pivotal DNA-repair gene, were related to the risk of HCC in Northeast China. Methods： One hundred and thirty six HCC patients and one hundred and thirty six frequency-matched controls were included in this hospital-based case-control study. Genotypes of UGT1A7 and XRCC1 were determined using allele-specific polymerase chain reaction （AS-PCR） and PCR-restriction fragment length polymorphism （RFLP）, and for which the odds ratio （OR） with 95% confidence interval （95% CI） were calculated. Results： The proportion of UGT1A7 low enzymatic allele （＊2 or ＊3） was higher in HCC patients than those in controls. The UGT1A7＊1/＊2 and ＊3/＊3 genotypes were associated with higher HCC risk （OR=2.09, 95%CI： 1.10-3.97; OR=5.67, 95%CI： 1.76-18.30, respectively）. The XRCC1 codon 399 Arg/Gln genotype could also elevate HCC risk （OR=2.16, 95% CI 1.29-3.61）. In addition to polymorphisms of UGT1A7 and XRCC1, multivariate logistic regression analysis demonstrated that other significant independent factors associated with HCC were HBV infection （OR=68.07, 95%CI： 28.03-165.26）, HCV infection （OR=30.97, 95%CI： 8.06-118.94） and family history of HCC （OR=10.62, 95%CI： 2.22-50.77）. Conclusion： The study shows that the polymorphisms of UGT1A7 and XRCC1 are associated with HCC risk. Determination of the polymorphisms of UGT1A7 and XRCC1 may provide an important clue to preventive measure against HCC.
基金Supported by a grant from the National Science Council, Taipei,Taiwan, China. No. NSC 92-2314-B-242-010
文摘AIM: Single nucleotide polymorphisms (SNPs) of uridinediphosphoglucuro -nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. We performed this research to establish the techniques for determining UGT1A7 gene and basic data of this gene for Taiwan Chinese. METHODS: We collected blood samples from 112 healthy adults and 505 subjects carrying different genotypes of UGT1A1, and determined the promoter area and the entire sequence of UGT1A7 exon 1 by polymerase chain reaction. We designed appropriate primers and restriction enzymes to detect variant UGT1A7 genotypes found in the study subjects. RESULTS: Six SNPs at nucleotides 33, 387, 391, 392, 622, and 756 within the coding region of UGT1A7 exon 1 were found. The incidence of UGT1A7*l/*2 (N129R131W208/ K129K131W208) was predominant (35.7%) while that of UGT1A7 *3/*3 (K129K131R208/K129K131R208) was the least (2.7%). The allele frequency of UGT1A7*3, which exists in a considerable proportion of Caucasians (0.361) and Japanese (0.255), was identified only to be 0.152 in our study subjects. A novel variation at nucleotide -57 in the upstream was found, which was associated with SNPs at nucleotides 33, 387, 391, 392, and 622 in one of the variant haplotypes. The nucleotide changes at positions 387, 391, 392 and 756 were in linkage in another variant haplotype. The allele frequency of UGT1A7*3 was 0.018, 0.158, 0.242, 0.433, and 0.920 in subjects carrying wild, A(TA)6TAA/A(TA)7TAA, A(TA)7TAA/A(TA)7TAA, 211G/211A, and 211A/211A variants of UGT1A1 gene, respectively. By using natural or mutagenesis primers, we successfully detected the variations at nucleotides -57, 33, 387, and 622 with the restriction enzymes HpyCH4 Ⅳ, TaqⅠ, AflⅡ, and Rsa Ⅰ, respectively. CONCLUSION: The results indicate that the allele frequencies of UGT1A7 gene in Taiwan Chinese are different from those in Caucasians and Japanese. Carriage of the nucleotide 211- variant UGT1A gene is highly associated with UGT1A7*3. The restriction-enzymedigestion method for the determination of nucleotides-57 (or 33, or 622) and 387 can rapidly identify genotypes of UGT1A7 in an individual.
