title: Differential expression and prognostic value of ERCC1 and thymidylate synthase in resected gastric adenocarcinoma.
abstract: BACKGROUND
  Excision repair cross-complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are associated with overall survival (OS) in several malignancies. Their expression patterns and prognostic value in resected gastric adenocarcinoma (GAC) are not known.
  
  
  METHODS
  In total, 109 patients who underwent resection for GAC between January 2000 and June 2011 had tissue available for analysis. The primary objective was to assess for the differential expression of ERCC1 and TS using immunohistochemistry. The secondary objective was to assess for the association between OS and the expression of ERCC1 and TS.
  
  
  RESULTS
  The median follow-up was 21.2 months, and the median OS was 28.8 months. Resected GAC exhibited differential expression of ERCC1 (high expression, 23%; n = 25) and TS (high expression, 43%; n = 47). ERCC1 and TS expression were not associated with OS. In a subset analysis of patients who received chemotherapy (n = 73), high ERCC1 expression was associated with decreased OS (16.7 months vs 53.8 months; P = 0.03). After controlling for known adverse pathologic features, high ERCC1 expression persisted as a negative prognostic factor in multivariate Cox regression analysis (hazard ratio, 2.5; 95% confidence interval, 1.03-6.0; P = .04). Conversely, in patients who underwent resection only (n = 35), high ERCC1 expression demonstrated a trend toward improved OS (40.4 months vs 12.7 months; P = .10); a positive prognostic influence also was present on multivariate analysis (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .03).
  
  
  CONCLUSIONS
  Resected GAC exhibited differential expression of TS and ERCC1. Among all patients, ERCC1 and TS expression levels were not associated with OS. High ERCC1 tumor expression was associated with decreased OS in the patients who received chemotherapy but was associated with increased OS in those who underwent surgery alone. ERCC1 expression had prognostic value in resected gastric cancer, and further investigation is warranted.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Malcolm H
authors.initials: MH
authors.lastname: Squires
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Fisher
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Fisher
authors.forename: Sameer H
authors.initials: SH
authors.lastname: Patel
authors.forename: David A
authors.initials: DA
authors.lastname: Kooby
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
authors.forename: Charles A
authors.initials: CA
authors.lastname: Staley
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: Shishir K
authors.initials: SK
authors.lastname: Maithel
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D004720:Endonucleases / Q000032:analysis* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery; D013940:Thymidylate Synthase / Q000032:analysis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases
keywords: ERCC1; biomarkers; gastric adenocarcinoma; thymidylate synthase