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Arch Pathol Lab Med. 2008 Nov;132(11):1746-52. doi: 10.1043/1543-2165-132.11.1746.

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

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Department of Pathology, Yale University, New Haven, CT 06511, USA.



Increased thymidylate synthase expression is a marker for decreased survival in colorectal cancer.


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.


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).


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.


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.

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