Jing Li1, Qianqian Yu1, Shengling Fu2, Min Xu1, Tao Zhang3, Conghua Xie4, Jueping Feng5, Jigui Chen6, Aihua Zang7, Yixin Cai2, Qiang Fu1, Shan Liu8, Mingsheng Zhang1, Qiu Hong1, Liu Huang9, Xianglin Yuan1. 1. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, People's Republic of China. 2. Department of Thoracic Surgery, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 3. Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 4. Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of China. 5. Wuhan Pu-Ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 6. Department of Surgery, Wuhan 8th Hospital, Wuhan, People's Republic of China. 7. Hubei Cancer Hospital, Wuhan, People's Republic of China. 8. The Second Clinical College, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 9. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, People's Republic of China. huangliu017@163.com.
Abstract
PURPOSE: UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD. METHODS: Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658). RESULTS: UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003). CONCLUSIONS: The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.
PURPOSE:UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD. METHODS: Six SNPs (TGFB1rs1800469; TGFBR1rs10733710, rs334354 and rs6478974; TGFBR2rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancerpatients treated with irinotecan in a prospective multicenter trial (NCT01282658). RESULTS:UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003). CONCLUSIONS: The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.
Authors: Rachel J Gibson; Joanne M Bowen; Mark R B Inglis; Adrian G Cummins; Dorothy M K Keefe Journal: J Gastroenterol Hepatol Date: 2003-09 Impact factor: 4.029