title: Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer.
abstract: OBJECTIVE
  The primary aim of this research was to investigate the association between uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms and the toxicities of irinotecan-based regimens in Chinese patients with metastatic colorectal cancer.
  
  
  METHODS
  The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The adverse reactions and tumor response were evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0, and Response Evaluation Criteria In Solid Tumors, Version 1.0, criteria, respectively. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia was analyzed. The influences of UGT1A1*6/*28 polymorphisms on response rate and progression-free survival were also analyzed. Survival analysis was performed by the Kaplan-Meier method, and we used the log-rank test to analyze the effect of genotypes on progression-free survival, the logistic regression model for multivariate analysis, and the Cox regression model for multivariate survival analysis.
  
  
  RESULTS
  A total of 167 patients with metastatic colorectal cancer who were treated with irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. The rate of UGT1A1*28 homozygous wild-type TA6/6, heterozygous mutant-type TA6/7, and homozygous mutant-type TA7/7 was 65.3% (109/167), 32.3% (54/167), and 2.4% (4/167), respectively; the incidence of UGT1A1*6 wild-type G/G was 67.1% (112/167), heterozygous mutant-type G/A accounted for 28.7% (48/167), and seven cases were homozygous mutant-type A/A (4.2%; 7/167). The incidence of grade 3 or 4 delayed diarrhea in patients carrying UGT1A1*6 (G/A and A/A) was higher than that in the wild-type (G/G) (P=0.021). The rate was significantly lower in patients with the UGT1A1*28 TA6/6 wide-type genotype than those with TA6/7 and TA7/7 mutant-type genotypes (P=0.027). However, neither UGT1A1*6 (P=0.34) nor UGT1A1*28 (P=0.232) variants were significantly associated with severe neutropenia. Our study found no significant differences of severe neutropenia in patients with different numbers of mutational alleles (P=0.354), but patients with two alleles or single allele variants had more chances to develop severe diarrhea than patients with wild-type (P=0.027). No significant differences of either response rate or progression-free survival were found among different genotypes (P>0.05).
  
  
  CONCLUSIONS
  For irinotecan-based regimens in metastatic colorectal cancer, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea, whereas no association between UGT1A1 gene polymorphisms and severe neutropenia was observed. We also found that neither clinical response nor prognosis were significantly associated with UGT1A1 gene polymorphisms.
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Zhehai
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Huan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Sun
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Fang
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Bi
keywords: gene polymorphism; irinotecan; metastatic colorectal cancer; uridine diphosphate glucuronosyltransferase 1A1