Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival

Hye Seung Lee, Min Chen, Ji Hun Kim, Woo Ho Kim, So Yeon Ahn, Kyungah Maeng, Carmen J. Allegra, Frederic J. Kaye, Steven N. Hochwald, Maria Zajac-Kaye

Research output: Contribution to journalArticle

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Abstract

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-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. What's new? The enzyme thymidylate synthase (TS) plays an essential role in cell proliferation. It may also promote tumorigenesis when overexpressed. In this study, the authors examined a large number of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and found that increased expression of TS was strongly associated with aggressive disease and early death. These results support the role of TS as a cancer-promoting agent in GEP-NET, and indicate that TS is a promising prognostic biomarker for these tumors. In addition, the authors found that p18 expression may predict survival in TS-positive patients who receive chemotherapy.

Original languageEnglish
Pages (from-to)128-137
Number of pages10
JournalInternational Journal of Cancer
Volume135
Issue number1
DOIs
StatePublished - 1 Jul 2014

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Thymidylate Synthase
Biomarkers
Survival
Neuroendocrine Tumors
Gastro-enteropancreatic neuroendocrine tumor
Tumor Biomarkers
Neoplasm Metastasis
DNA Repair Enzymes
Drug Therapy
cdc Genes
Neoplasms
Protein Array Analysis

Keywords

  • gastroenteropancreatic neuroendocrine tumor
  • immunohistochemistry
  • survival analysis
  • thymidylate synthase

Cite this

Lee, Hye Seung ; Chen, Min ; Kim, Ji Hun ; Kim, Woo Ho ; Ahn, So Yeon ; Maeng, Kyungah ; Allegra, Carmen J. ; Kaye, Frederic J. ; Hochwald, Steven N. ; Zajac-Kaye, Maria. / Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival. In: International Journal of Cancer. 2014 ; Vol. 135, No. 1. pp. 128-137.
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title = "Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival",
abstract = "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-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. What's new? The enzyme thymidylate synthase (TS) plays an essential role in cell proliferation. It may also promote tumorigenesis when overexpressed. In this study, the authors examined a large number of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and found that increased expression of TS was strongly associated with aggressive disease and early death. These results support the role of TS as a cancer-promoting agent in GEP-NET, and indicate that TS is a promising prognostic biomarker for these tumors. In addition, the authors found that p18 expression may predict survival in TS-positive patients who receive chemotherapy.",
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Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival. / Lee, Hye Seung; Chen, Min; Kim, Ji Hun; Kim, Woo Ho; Ahn, So Yeon; Maeng, Kyungah; Allegra, Carmen J.; Kaye, Frederic J.; Hochwald, Steven N.; Zajac-Kaye, Maria.

In: International Journal of Cancer, Vol. 135, No. 1, 01.07.2014, p. 128-137.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival

AU - Lee, Hye Seung

AU - Chen, Min

AU - Kim, Ji Hun

AU - Kim, Woo Ho

AU - Ahn, So Yeon

AU - Maeng, Kyungah

AU - Allegra, Carmen J.

AU - Kaye, Frederic J.

AU - Hochwald, Steven N.

AU - Zajac-Kaye, Maria

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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-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. What's new? The enzyme thymidylate synthase (TS) plays an essential role in cell proliferation. It may also promote tumorigenesis when overexpressed. In this study, the authors examined a large number of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and found that increased expression of TS was strongly associated with aggressive disease and early death. These results support the role of TS as a cancer-promoting agent in GEP-NET, and indicate that TS is a promising prognostic biomarker for these tumors. In addition, the authors found that p18 expression may predict survival in TS-positive patients who receive chemotherapy.

AB - 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-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. What's new? The enzyme thymidylate synthase (TS) plays an essential role in cell proliferation. It may also promote tumorigenesis when overexpressed. In this study, the authors examined a large number of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and found that increased expression of TS was strongly associated with aggressive disease and early death. These results support the role of TS as a cancer-promoting agent in GEP-NET, and indicate that TS is a promising prognostic biomarker for these tumors. In addition, the authors found that p18 expression may predict survival in TS-positive patients who receive chemotherapy.

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KW - immunohistochemistry

KW - survival analysis

KW - thymidylate synthase

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