{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:26:59Z","timestamp":1788877619459,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,1,6]],"date-time":"2014-01-06T00:00:00Z","timestamp":1388966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:p>Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki\u201067, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP\u2010NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT\u2010PCR was used to validate these findings. We found that 78 of 320 GEP\u2010NETs (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\u2010NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Patients with TS\u2010positive NETs had markedly worse outcomes than TS\u2010negative NETs as shown by univariate (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and multivariate (<jats:italic>p<\/jats:italic>\u2009=\u20090.01) survival analyses. Expression of p18 predicted survival in TS\u2010positive patients that received chemotherapy (<jats:italic>p<\/jats:italic>\u2009=\u20090.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP\u2010NETs. 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.<\/jats:p>","DOI":"10.1002\/ijc.28675","type":"journal-article","created":{"date-parts":[[2013,12,18]],"date-time":"2013-12-18T09:57:11Z","timestamp":1387360631000},"page":"128-137","source":"Crossref","is-referenced-by-count":20,"title":["Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival"],"prefix":"10.1002","volume":"135","author":[{"given":"Hye Seung","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pathology Seoul National University Bundang Hospital Seongnam Gyeonggi Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Florida College of Medicine Gainesville 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