Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy

Watson, Roshawn G.; Muhale, Filipe; Thorne, Leigh B.; Yu, Jinsheng; O’Neil, Bert H.; Hoskins, Janelle M.; Meyers, Michael O.; Deal, Allison M.; Ibrahim, Joseph G.; Hudson, Michael L.; Walko, Christine M.; McLeod, Howard L.; Auman, James T.

doi:10.1016/j.ejca.2010.07.011

« Previous Next »European Journal of Cancer
Volume 46, Issue 18 , Pages 3358-3364, December 2010

Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy

Roshawn G. Watson
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Filipe Muhale
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Leigh B. Thorne
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jinsheng Yu
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Bert H. O’Neil
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Janelle M. Hoskins
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Michael O. Meyers
- Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Allison M. Deal
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Joseph G. Ibrahim
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Michael L. Hudson
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Christine M. Walko
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Howard L. McLeod
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
James T. Auman
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Corresponding author: Address: UNC Institute for Pharmacogenomics and Individualized Therapy, 120 Mason Farm Rd., Campus Box # 7361, Chapel Hill, NC 27599, USA. Tel.: +1 919 966 6995; fax: +1 919 966 5863.

Received 28 April 2010; received in revised form 18 June 2010; accepted 14 July 2010. published online 20 August 2010.

Abstract

Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p=0.036). No significant differences were noted in TYMP copy number alterations between 5-FU-exposed and -unexposed metastases. Median survival time was similar in 5-FU-exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio=2.7, 95% confidence interval=1.1–6.6; p=0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.