186例消化系统恶性肿瘤患者UGT1A1~*6、UGT1A1~*28基因多态性的检测和分析
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摘要
目的:检测和分析消化系统恶性肿瘤患者UGT1A1*6、UGT1A1*28基因多态性。方法:收集186例消化系统恶性肿瘤患者血液标本,采用焦磷酸测序方法对UGT1A1*6、UGT1A1*28基因多态性进行检测,并对基因多态性频率进行统计分析。结果:186例消化系统恶性肿瘤患者样本具有群体代表性。UGT1A1*6基因多态性为野生型G/G占比63.4%、杂合型G/A占比32.8%、突变纯合型AA占比3.8%;UGT1A1*28基因多态性为野生型TA6/TA6占比75.8%、杂合型TA6/TA7占比21.5%、突变纯合型TA7/TA7占比2.7%;UGT1A1*6和*28基因多态性为野生型G/G且TA6/TA6占比48.9%,单点变异型G/G且TA6/TA7占比12.4%、G/A且TA6/TA6占比23.1%,双点变异型G/G且TA7/TA7占比2.2%、G/A且TA6/TA7占比9.1%、A/A且TA6/TA6占比3.8%,三点变异型G/A且TA7/TA7占比0.5%。患者UGT1A1*6与UGT1A1*28基因多态性频率分布之间具有显著性差异(P<0.05)。3个不同年龄段患者之间,胃癌、结直肠癌、其他消化系统恶性肿瘤患者之间的UGT1A1*28、UGT1A1*6和*28基因型分布具有显著性差异(P<0.05)。结论:消化系统恶性肿瘤患者应用伊立替康时,应联合检测UGT1A1*6和UGT1A1*28基因多态性,同时密切关注患者的肿瘤类型以及年龄差异。
OBJECTIVE To detect and analyze the gene polymorphisms of UGT1A1*6 and UGT1A1*28 in patients with digestive system malignant tumors.METHODS Blood samples from186 patients with digestive system malignant tumors were collected.The gene polymorphisms of UGT1A1*6 and UGT1A1*28 were detected by pyrophosphate sequencing,and the frequencies of gene polymorphisms were analyzed statistically.RESULTS The samples from186 patients with digestive system malignant tumors were representative of the population.In186 patients with digestive system malignant tumors,the frequencies of UGT1A1*6 gene polymorphism carrying G/G,G/A and A/A genotype were 63.4%,32.8% and 3.8%,respectively.The frequencies of UGT1A1*28 gene polymorphism carrying TA6/TA6,TA6/TA7 and TA7/TA7 genotype were 75.8%,21.5%and 2.7%,respectively.The frequencies of UGT1A1*6 and*28 gene polymorphism carrying G/G TA6/TA6,G/G TA6/TA7,G/A TA6/TA6,G/G TA7/TA7,G/A TA6/TA7,A/A TA6/TA6 and G/A TA7/TA7 genotype were 48.9%,12.4%,23.1%,2.2%,9.1%,3.8% and 0.5%,respectively.The distributions of genotype between UGT1A1*6 and UGT1A1*28 in patients with malignant tumors was significantly different(P<0.05).The distribution of UGT1A1*28 genotype among patients in three different levels of age was significantly different,as well as the distribution of UGT1A1*6 and*28 genotype(P<0.05).The distributions of UGT1A1*28 genotype among patients with gastric cancer,colorectal cancer and other digestive system malignant tumors were significantly different,as well as the distributions of UGT1A1*6 and*28 genotype(P<0.05).CONCLUSION Combined detection of UGT1A1*6 and UGT1A1*28 would help identification and subsequent evaluation of irinotecan therapy in patients with digestive system malignant tumors,and attention should be paid to the tumor types and age levels.
OBJECTIVE To detect and analyze the gene polymorphisms of UGT1A1*6 and UGT1A1*28 in patients with digestive system malignant tumors.METHODS Blood samples from186 patients with digestive system malignant tumors were collected.The gene polymorphisms of UGT1A1*6 and UGT1A1*28 were detected by pyrophosphate sequencing,and the frequencies of gene polymorphisms were analyzed statistically.RESULTS The samples from186 patients with digestive system malignant tumors were representative of the population.In186 patients with digestive system malignant tumors,the frequencies of UGT1A1*6 gene polymorphism carrying G/G,G/A and A/A genotype were 63.4%,32.8% and 3.8%,respectively.The frequencies of UGT1A1*28 gene polymorphism carrying TA6/TA6,TA6/TA7 and TA7/TA7 genotype were 75.8%,21.5%and 2.7%,respectively.The frequencies of UGT1A1*6 and*28 gene polymorphism carrying G/G TA6/TA6,G/G TA6/TA7,G/A TA6/TA6,G/G TA7/TA7,G/A TA6/TA7,A/A TA6/TA6 and G/A TA7/TA7 genotype were 48.9%,12.4%,23.1%,2.2%,9.1%,3.8% and 0.5%,respectively.The distributions of genotype between UGT1A1*6 and UGT1A1*28 in patients with malignant tumors was significantly different(P<0.05).The distribution of UGT1A1*28 genotype among patients in three different levels of age was significantly different,as well as the distribution of UGT1A1*6 and*28 genotype(P<0.05).The distributions of UGT1A1*28 genotype among patients with gastric cancer,colorectal cancer and other digestive system malignant tumors were significantly different,as well as the distributions of UGT1A1*6 and*28 genotype(P<0.05).CONCLUSION Combined detection of UGT1A1*6 and UGT1A1*28 would help identification and subsequent evaluation of irinotecan therapy in patients with digestive system malignant tumors,and attention should be paid to the tumor types and age levels.
引文
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[13]Lin MH,Liu J,Zhou HL,et al.Effects of UDP-glucuronosyltransferase(UGT)polymorphisms on the pharmacokinetics of febuxostat in healthy Chinese volunteers[J].Drug Metab Pharmacok,2017,32(1):77-84.
[14]Huang CJ,Zhang H.Analysis on gene polymorphism of UGT1A1*28in 282 cases of colorectal cancer[J].Int J Lab Med(国际检验医学杂志),2015,36(9):1173-1175.
[15]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[J].Cancer Sci,2007,98(9):1461-1467.
[16]Wang Y,Shen L,Xu N,et al.UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil[J].World J Gastroenterol,2012,18(45):6635-6644.
[17]Minami H,Sai K,Saeki M,et al.Irinotecan pharmacokinetics/pharmacodynamics and UGT1Agenetic polymorphisms in Japanese:roles of UGT1A1*6 and*28[J].Pharmacogenet Genomics,2007,17(7):497-504.
[18]Atasilp C,Chansriwong P,Sirachainan E,et al.Correlation of UGT1A1*28 and*6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients[J].Drug Metab Pharmacok,2015,31(1):90-94.
[19]Zhou CF,Ma T,Su Y,et al.UGT1A1 gene polymorphisms and the toxicities of FOLFIRI in Chinese Han patients with gastrointestinal cancer[J].Anti-cancer Agents Med Chem,2013,13(2):235-241.
[20]Lai XY,Heng XY,Che FY,et al.Frequency of UGT1A1*28and UGT1A1*6 gene polymorphisms in cancer patients in some areas of China[J].Chin Gen Pract(中国全科医学),2016,19(30):3705-3710.
[21]Zhang Y,Su D,Guo XC,et al.Relationship between UGT1A1*28 and UGT1A1*6 gene polymorphism and adverse reactions of irinotecan-based chemotherapy[J].Acad J Chin PLA Med Sch(解放军医学院学报),2014,35(5):489-492,495.
[22]Yin H,Gao Y.Correlation between gene polymorphisms of UGT1A1*28 and UGT1A1*6 and adverse reactions of irinotecan chemotherapy in Chinese patients[J].Jiangsu Med J(江苏医药),2014,40(19):2307-2309.
[23]Girard H,Butler LM,Villeneuve L,et al.UGT1A1 and UGT1A9 functional variants,meat intake,and colon cancer,among Caucasians and African Americans[J].Mutat Res-Fund Mol M,2008,644(1-2):56-63.
[2]Shimada S,Yagi Y,Kuramoto M,et al.Second-line chemotherapy with combined irinotecan and low-dose cisplatin for patients with metastatic gastric carcinoma resistant to 5-fluorouracil[J].Oncol Rep,2003,10(3):687-691.
[3]Rhodes KE,Zhang W,Yang DY,et al.ABCB1,SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan[J].Drug Metab Lett,2007,1(1):23-30.
[4]Meech R,Mackenzie PI.Structure and function of uridine diphosphate glucuronosyltransferases[J].Clin Exp Pharmacol Physiol,1997,24(12):907-915.
[5]Yang C,Liu Y,Xi WQ,et al.Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecancontaining regimens[J].Drug Des Dev Ther,2015,9:3677-3683.
[6]Ando Y,Saka H,Ando M,et al.Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity:A pharmacogenetic analysis[J].Cancer Res,2000,60(24):6921-6926.
[7]Teh LK,Hashim H,Zakaria ZA,et al.Polymorphisms of UGT1A1*6,UGT1A1*27&UGT1A1*28in three major ethnic groups from Malaysia[J].Indian J Med Res,2012,136(2):249-259.
[8]Han FF,Guo CL,Yu D,et al.Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients[J].Cancer Chemother Pharmcol,2014,73(4):779-788.
[9]Bandrés E,Zárate R,Ramirez N,et al.Pharmacogenomics in colorectal cancer:The first step for individualized-therapy[J].World J Gastroenterol,2007,13(44):5888-5901.
[10]Fakih MG,Ross ME,Starostik P.Increased frequency of uridine diphosphate glucuronosyltransferase 1A1 7/7 in patients experiencing severe irinotecan-induced toxicities[J].Clin Colorectal Cancer,2007,6(8):583-587.
[11]Kweekel DM,Gelderblom H,Van der Straaten T,et al.UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer:a Dutch Colorectal Cancer Group study[J].Brit J Cancer,2008,99(2):275-282.
[12]Palomaki GE,Bradley LA,Douglas MP,et al.Can UGT1A1genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?An evidencebased review[J].Genet Med,2009,11(1):21-34.
[13]Lin MH,Liu J,Zhou HL,et al.Effects of UDP-glucuronosyltransferase(UGT)polymorphisms on the pharmacokinetics of febuxostat in healthy Chinese volunteers[J].Drug Metab Pharmacok,2017,32(1):77-84.
[14]Huang CJ,Zhang H.Analysis on gene polymorphism of UGT1A1*28in 282 cases of colorectal cancer[J].Int J Lab Med(国际检验医学杂志),2015,36(9):1173-1175.
[15]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[J].Cancer Sci,2007,98(9):1461-1467.
[16]Wang Y,Shen L,Xu N,et al.UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil[J].World J Gastroenterol,2012,18(45):6635-6644.
[17]Minami H,Sai K,Saeki M,et al.Irinotecan pharmacokinetics/pharmacodynamics and UGT1Agenetic polymorphisms in Japanese:roles of UGT1A1*6 and*28[J].Pharmacogenet Genomics,2007,17(7):497-504.
[18]Atasilp C,Chansriwong P,Sirachainan E,et al.Correlation of UGT1A1*28 and*6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients[J].Drug Metab Pharmacok,2015,31(1):90-94.
[19]Zhou CF,Ma T,Su Y,et al.UGT1A1 gene polymorphisms and the toxicities of FOLFIRI in Chinese Han patients with gastrointestinal cancer[J].Anti-cancer Agents Med Chem,2013,13(2):235-241.
[20]Lai XY,Heng XY,Che FY,et al.Frequency of UGT1A1*28and UGT1A1*6 gene polymorphisms in cancer patients in some areas of China[J].Chin Gen Pract(中国全科医学),2016,19(30):3705-3710.
[21]Zhang Y,Su D,Guo XC,et al.Relationship between UGT1A1*28 and UGT1A1*6 gene polymorphism and adverse reactions of irinotecan-based chemotherapy[J].Acad J Chin PLA Med Sch(解放军医学院学报),2014,35(5):489-492,495.
[22]Yin H,Gao Y.Correlation between gene polymorphisms of UGT1A1*28 and UGT1A1*6 and adverse reactions of irinotecan chemotherapy in Chinese patients[J].Jiangsu Med J(江苏医药),2014,40(19):2307-2309.
[23]Girard H,Butler LM,Villeneuve L,et al.UGT1A1 and UGT1A9 functional variants,meat intake,and colon cancer,among Caucasians and African Americans[J].Mutat Res-Fund Mol M,2008,644(1-2):56-63.