title: AQUA analysis of thymidylate synthase reveals localization to be a key prognostic biomarker in 2 large cohorts of colorectal carcinoma.
abstract: BACKGROUND
  Increased thymidylate synthase expression is a marker for decreased survival in colorectal cancer.
  
  
  OBJECTIVE
  Thymidylate synthase localizes to both the nucleus and cytoplasm, but how the relationship of these expression levels affects colon cancer outcome has yet to be determined.
  
  
  METHODS
  Using AQUA, we assessed prognosis of thymidylate synthase expression as a function of subcellular localization in 2 retrospective cohorts of colorectal carcinoma. We used the first cohort (n = 599) as a training set, subsequently validating optimal expression cut points in the second cohort (n = 447).
  
  
  RESULTS
  A significant association between decreased 5-year disease-specific survival and increased nuclear expression (16% decreased survival [72% to 56%] for the top 60% of nuclear-expressing tumors [P < .001]) and cytoplasmic expression (12% decreased survival [70% to 58%] for the top 54% of cytoplasmic-expressing tumors [P = .02]) was observed for the training set. A higher nuclear to cytoplasmic ratio also correlated significantly with decreased survival (15% decreased survival [66% to 51%] for the top 25% of tumors [P < .001]). Applying these findings to the validation set, as a function of time to recurrence, only the ratio (P = .03 [expression ratio]; P = .18 [nuclear]; P = .71 [cytoplasmic]) showed a significant association with decreased time to recurrence. Additionally, the expression ratio significantly added to the prognostic value given by the primary tumor pathologic classification and nodal status.
  
  
  CONCLUSIONS
  These data suggest the relationship of nuclear to cytoplasmic thymidylate synthase expression, given as a ratio of continuous AQUA scores, to be a strong predictor of colon cancer survival.
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06511, USA. mgustavson@historx.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gustavson
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.forename: Greg
authors.initials: G
authors.lastname: Tedeschi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Camp
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006652:Histological Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase