title: UGT1A1 gene polymorphisms and the toxicities of FOLFIRI in Chinese Han patients with gastrointestinal cancer.
abstract: BACKGROUND
  Neutropenia and diarrhea are the common dose-limiting toxicities of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan related toxicities. This study aims to investigate the association between UGT1A1 gene polymorphisms and irinotecan related toxicities in Chinese Han gastrointestinal cancer patients receiving FOLFIRI regimen chemotherapy.
  
  
  METHODS
  A total of 94 gastrointestinal cancer patients with metastasis (72 colon and rectum, 20 stomach, 1 pancreas and 1 duodenum), were enrolled from 2007 to 2010 in Shanghai Ruijin Hospital. All patients received standard dosage of FOLFIRI regimen (irinotecan 180mg/m2 d1, CF 200mg/m2 d1-d2, 5-FU 400mg/m2 d1-d2, followed by continuous infusion of 5-FU 600mg/m2 for 22h d1-d2, every 2 weeks). UGT1A1 gene polymorphisms (*60 -3279T > G, *93 -3156G > A, *28 -53TA6 > TA7, *6 211G > A) were detected by direct sequencing of DNA extracted from peripheral blood. The incidence of neutropenia, diarrhea, and time to severe toxicity were recorded. The relationship between UGT1A1 gene polymorphisms and toxicities was analyzed.
  
  
  RESULTS
  The frequencies of UGT1A1*60 (-3279 G/G), UGT1A1*93 (-3156 A/A), UGT1A1*28 (-53 7/7) and UGT1A1*6 (211 A/A) homozygote were 6.4% (6/94), 1.1% (1/94), 1.1% (1/94) and 2.1% (2/94), respectively. The incidences of grade 3/4 neutropenia and diarrhea were 53.2% (50/94) and 12.8% (12/94), respectively. Comparing those with wild type, patients with UGT1A1*28 or *93 allele had significantly high risk of grade 3/4 diarrhea (6/7, 7/7 vs. 6/6: 27.8% vs. 9.2%, OR=3.791, P=0.034; G/A, A/A vs. G/G: 29.4% vs. 9.1%, OR=4.167, P=0.023). No relationship was found between UGT1A1 allele polymorphism and grade 3/4 neutropenia. The baseline serum total bilirubin was elevated in UGT1A1*28, *93 allele carriers and *60 homozygote, but with no relationship with severe toxicities.
  
  
  CONCLUSIONS
  In Chinese Han gastrointestinal cancer patients receiving standard FOLFIRI regimen, UGT1A1*28 or *93 allele carriers may have high risk of severe diarrhea.
authors.affiliation: Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China.
authors.forename: Chen-fei
authors.initials: CF
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Zheng-bao
authors.initials: ZB
authors.lastname: Ye
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.forename: Ying-yan
authors.initials: YY
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Bing-ya
authors.initials: BY
authors.lastname: Liu
authors.forename: Zheng-gang
authors.initials: ZG
authors.lastname: Zhu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D003967:Diarrhea / Q000139:chemically induced*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme