title: Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage II/III gastric cancer.
abstract: BACKGROUND
  The efficacy of 5-fluorouracil (5FU)-based therapy, which remains the cornerstone of gastrointestinal cancer treatment, depends upon the expression of enzymes involved in pyrimidine metabolism, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT). We analyzed the expression of these genes in patients enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) and their possible roles as biomarkers for treatment outcomes.
  
  
  METHODS
  Formalin-fixed, paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3 %) patients. TS, DPD, TP, and OPRT expression was measured by RT-PCR in manually microdissected tumor specimens and normalized to the reference gene, β-actin. The expression level of each gene was categorized as low or high using cutoffs at the 33.3rd, 50th, or 66.7th percentiles.
  
  
  RESULTS
  The hazard ratio (HR) for overall survival (OS) after S-1 treatment versus surgery alone was significantly lower in high (>66.7th percentile; HR = 0.370; 95 % CI 0.221-0.619) compared to low (<66.7th percentile; HR = 0.757; 95 % CI 0.563-1.018) TS expression groups (P = 0.015). Similarly, the HR for OS after S-1 therapy versus surgery alone was significantly lower in high (>33.3rd percentile; HR = 0.520, 95 % CI 0.376-0.720) compared to low (<33.3rd percentile; HR = 0.848, 95 % CI 0.563-1.276) DPD expression groups (P = 0.065). There was no interaction between TP or OPRT expression and OS.
  
  
  CONCLUSIONS
  This large biomarker study showed that high TS and DPD gene expression in tumors was associated with enhanced benefit from postoperative adjuvant S-1 treatment in gastric cancer. There was no interaction between TP and OPRT expression and S-1 treatment.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan, msasako@hyo-med.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasako
authors.forename: Masanori
authors.initials: M
authors.lastname: Terashima
authors.forename: Wataru
authors.initials: W
authors.lastname: Ichikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.forename: Koji
authors.initials: K
authors.lastname: Kitada
authors.forename: Issei
authors.initials: I
authors.lastname: Kurahashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sakuramoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imamura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D004338:Drug Combinations; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D010094:Oxonic Acid / Q000627:therapeutic use; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005641:Tegafur / Q000627:therapeutic use; D013939:Thymidine Phosphorylase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase
references.citation: Histopathology. 2008 Jun;52(7):797-805
references.pmid: 18422971
references.citation: Clin Cancer Res. 2012 Nov 1;18(21):5992-6000
references.pmid: 22977193
references.citation: Eur J Cancer. 2003 Nov;39(16):2387-94
references.pmid: 14556932
references.citation: N Engl J Med. 2007 Nov 1;357(18):1810-20
references.pmid: 17978289
references.citation: J Clin Oncol. 1996 Jan;14(1):176-82
references.pmid: 8558194
references.citation: Int J Mol Med. 2000 Feb;5(2):133-8
references.pmid: 10639590
references.citation: Br J Cancer. 2008 Feb 26;98(4):832-9
references.pmid: 18231104
references.citation: Eur J Cancer. 2002 Jun;38(9):1271-7
references.pmid: 12044515
references.citation: J Clin Oncol. 2004 Feb 1;22(3):529-36
references.pmid: 14752076
references.citation: Cancer Res. 1986 Jan;46(1):20-8
references.pmid: 2415245
references.citation: Pharmacogenet Genomics. 2009 Dec;19(12):955-64
references.pmid: 19898266
references.citation: Gastric Cancer. 2006;9(3):145-55
references.pmid: 16952032
references.citation: J Clin Oncol. 2010 Sep 1;28(25):3937-44
references.pmid: 20679606
references.citation: J Natl Cancer Inst. 2005 Aug 17;97(16):1180-4
references.pmid: 16106022
references.citation: Oncol Rep. 2005 Nov;14(5):1223-30
references.pmid: 16211289
references.citation: Gan To Kagaku Ryoho. 2000 Jun;27(6):891-8
references.pmid: 10897217
references.citation: Ann Oncol. 2006 Dec;17(12):1818-25
references.pmid: 16980606
references.citation: Nature. 2007 Oct 4;449(7162):557-63
references.pmid: 17914389
references.citation: Eur J Cancer. 2009 Jul;45(11):1935-49
references.pmid: 19473832
references.citation: Biochim Biophys Acta. 1977 Dec 23;473(2):73-92
references.pmid: 145246
references.citation: Ann Oncol. 2013 May;24(5):1253-61
references.pmid: 23233651
references.citation: Clin Cancer Res. 2000 Dec;6(12):4797-802
references.pmid: 11156237
references.citation: Clin Cancer Res. 1999 Oct;5(10):2672-3
references.pmid: 10537327
references.citation: J Clin Oncol. 2002 Apr 1;20(7):1721-8
references.pmid: 11919227
references.citation: Anticancer Drugs. 1996 Jul;7(5):548-57
references.pmid: 8862723
references.citation: J Clin Oncol. 2011 Nov 20;29(33):4387-93
references.pmid: 22010012
references.citation: Clin Cancer Res. 1998 Oct;4(10):2371-6
references.pmid: 9796967
references.citation: Nature. 2006 Jun 22;441(7096):1015-9
references.pmid: 16791201
references.citation: Lancet. 2012 Jan 28;379(9813):315-21
references.pmid: 22226517
references.citation: Clin Cancer Res. 2003 Sep 15;9(11):4116-24
references.pmid: 14519634
references.citation: Gastric Cancer. 1998 Dec;1(1):10-24
references.pmid: 11957040
references.citation: Anticancer Res. 1999 Nov-Dec;19(6C):5635-40
references.pmid: 10697632