CAJ | 학술논문

背景与目的：尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyl transferase 1A1，UGTlA1)是伊立替康代谢关键酶，其活性受基因多态性影响显著。本研究探讨结直肠癌患者中，UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法：入组2013年4月-2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA，分别采用STR方法和Sanger测序法，检测UGT1A1*28和UGT1A1*6基因型，分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访，记录不良反应发生情况和严重程度，比较不同基因型患者之间的差异。结果：160例消化道肿瘤患者中，UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%)；杂合子TA6/733例(20.5%)；纯合子TA7/73例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%)，杂合子GA 48例(30.0%)；纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中，*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3% vs 0.0%，P<0.001)，并增加整体不良反应发生率(76.0% vs 45.6%，P<0.001)；*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论：接受伊立替康化疗的结直肠癌患者，UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险，可预测伊立替康引起的骨髓抑制性不良反应，辅助临床选择合适的化疗方案。
배경여목적：뇨감이린산포도당철산전이매1A1(uridine diphosphoglucu-ronosyl transferase 1A1，UGTlA1)시이립체강대사관건매，기활성수기인다태성영향현저。본연구탐토결직장암환자중，UGT1A1*28화UGT1A1*6기인다태성여이립체강치료상관불량반응지간적관계。방법：입조2013년4월-2013년12월우복단대학부속중산의원종류내과접수치료적소화도악성종류환자160례。추제외주혈중기인조DNA，분별채용STR방법화Sanger측서법，검측UGT1A1*28화UGT1A1*6기인형，분석UGT1A1기인다태성분포정황。대기중82례화료방안중함이립체강적결직장암환자진행수방，기록불량반응발생정황화엄중정도，비교불동기인형환자지간적차이。결과：160례소화도종류환자중，UTG1A1*28(계동자TATA합구역TA중복차수)야생형TA6/6124례(77.5%)；잡합자TA6/733례(20.5%)；순합자TA7/73례(2.0%)。UGT1A1*6위점(211G>A)야생형GG 105례(65.6%)，잡합자GA 48례(30.0%)；순합자AA 7례(4.4%)。82례화료방안중함이립체강적결직장암환자중，*28기인형(TA6/7화TA7/7)현저증가발생3급이상중성립세포감소적풍험(58.3% vs 0.0%，P<0.001)，병증가정체불량반응발생솔(76.0% vs 45.6%，P<0.001)；*6기인형(GA화AA)、년령、성별、화료방안화이립체강상관불량반응발생무현저상관성。결론：접수이립체강화료적결직장암환자，UGT1A1*28위점다태성현저증가중성립세포감소발생적풍험，가예측이립체강인기적골수억제성불량반응，보조림상선택합괄적화료방안。
Background and purpose: Uridine diphosphoglucu-ronosyl transferase 1A1 (UGT1A1) is an important enzyme for metabolism of irinotecan. The activity of UGT1A1 enzyme was significantly affected by the gene polymorphism. This study aimed to investigate the correlation of UGT1A1*28 and *6 gene polymorphisms with irinotecan-based chemotherapy in colorectal cancer(CRC). Methods: Analysis of UGT1A1*28 and *6 gene polymorphisms was performed in 160 gastrointestinal cancer patients admitted to Zhongshan Hospital Fudan University from Apr. 2013 to Dec. 2013 by amplifying the gene fragments using PCR, STR and Sanger sequencing. Eighty-two cases with CRC treated with irinotecan were chosen to observe the adverse events during chemotherapy. The incidence of different genotypes was compared. Results:The distribution of the genotypes in 160 gastrointestinal cancer patients was as followed:UGT1A1*28 wild-type genotype TA6/6 (124, 77.5%), heterozygous genotype TA6/7 (33, 20.5%), and homozygous genotype TA7/7 (3, 2.0%);UGT1A1*6 wild-type genotype GG (105, 65.6%), heterozygous genotype GA (48, 30.0%), and homozygous genotype AA (7, 4.4%). In the 82 CRC cases, the incidences of grade 3 and 4 neutropenia in the patients carrying UGT1A1*28 (TA6/7+TA7/7 ) were higher than those in the WT genotype (TA6/6) (58.3%vs 0.0, P<0.001), and increased the total incidence of adverse events (76.0%vs 45.6%, P<0.001). There was no signiifcant relevance between UGT1A1*6 genotype, age, gender chemotherapy and adverse events. Conclusion:In the CRC cases with irinotecan-based chemotherapy, the UGT1A1*28 (TA6/7+TA7/7) genotype signiifcantly increased the risk of grade 3 and 4 neutropenia. Detecting UGT1A1 gene polymorphisms may guide individualized treatment and predict adverse events.