Publication Date:
2013-12-19
Description:
Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair is both a potential tumor prognostic biomarker as well as a tumorgenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results with other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27, and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach, and pancreas showed the highest expression of TS (47.4%, 42.6%, and 37.3%, respectively), whereas NETs of the appendix, rectum, and duodenum displayed low TS expression (3.3%, 12.9%, and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis, and distant metastasis (p 〈 0.05). Patients with TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p 〈 0.001) and multivariate (p = 0.01) survival analyses. Expression of p18 predicted survival in TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors. © 2013 Wiley Periodicals, Inc.
Print ISSN:
0020-7136
Electronic ISSN:
1097-0215
Topics:
Biology
,
Medicine
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