title: A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Thoracic Surgery, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Shengling
authors.initials: S
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of China.
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
authors.affiliation: Wuhan Pu-Ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Jueping
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Surgery, Wuhan 8th Hospital, Wuhan, People's Republic of China.
authors.forename: Jigui
authors.initials: J
authors.lastname: Chen
authors.affiliation: Hubei Cancer Hospital, Wuhan, People's Republic of China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zang
authors.affiliation: Department of Thoracic Surgery, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Cai
authors.affiliation: 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.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: The Second Clinical College, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Liu
authors.initials: L
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Yuan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D016212:Transforming Growth Factor beta / Q000235:genetics*; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D016212:Transforming Growth Factor beta; D000099148:UGT1A1 Enzyme
keywords: Colorectal cancer; Diarrhea; Genotype; Irinotecan; TGFB