AQUA analysis of thymidylate synthase reveals localization to be a key prognostic biomarker in 2 large cohorts of colorectal carcinoma

Arch Pathol Lab Med. 2008 Nov;132(11):1746-52. doi: 10.5858/132.11.1746.

Abstract

Context: 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.

Design: 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.

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cohort Studies
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytoplasm / metabolism*
  • Cytoplasm / pathology
  • Female
  • Histological Techniques
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Microarray Analysis
  • Middle Aged
  • Multivariate Analysis
  • Prognosis
  • Retrospective Studies
  • Thymidylate Synthase / metabolism*

Substances

  • Biomarkers, Tumor
  • Thymidylate Synthase