Polymorphic Thymidylate Synthase Gene Impacts on Overall Survival of Patients with Epithelial Ovarian Cancer After Platinum-Based Chemotherapy

Abstract

Aim: High levels of TS have been associated with a worse clinical outcome in several cancers including epithelial ovarian cancer (EOC). The TS gene (TYMS) is highly polymorphic and has an effect on mRNA/protein expression. Materials & methods: Six TYMS polymorphisms were investigated for overall survival (OS) in 216 EOC patients: TYMS 1494ins/del, TSER (variable number of tandem repeats of 28 bp), TSER G>C, TYMS 1053C>T, TYMS IVS6-68C>T and TYMS 1122A>G. Results: In a multivariate analysis, TYMS 1494 del/del genotype was associated with a significant increased OS compared with the ins/ins genotype (hazard ratio: 0.36; 95% CI: 0.16–0.82, p = 0.01). Similar results were obtained for the mutant genotypes TYMS 1053TT and TYMS IVS6-68TT. The event-free survival was significantly higher in TYMS 1053TT patients compared with wild-type patients (p = 0.05). Conclusion:TYMS 1494ins/del, 1053C>T and IVS6-68C>T polymorphisms can be prognostic markers for OS in patients with EOC, independently from stage at diagnosis, median age and tumor histotype.

Original submitted 11 May 2012; Revision submitted 10 August 2012

KEYWORDS::

• EOC
• epithelial ovarian cancer
• OS
• overall survival
• platinum
• polymorphism
• thymidylate synthase
• TYMS

Acknowledgements

The authors thank A Vallerugo, MA, USA, for her assistance in preparation of the manuscript.

Financial & competing interests disclosure

The authors thank Associazione Italiana per la Ricerca sul Cancro (AIRC), Special Program Molecular Clinical Oncology, 5x1000, (No. 12214), European Research Council, Programme ideas, Proposal No 269051 Italian Ministry of Education MIUR (FIRB prot. RBAP11ETKA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The authors thank Associazione Italiana per la Ricerca sul Cancro (AIRC), Special Program Molecular Clinical Oncology, 5x1000, (No. 12214), European Research Council, Programme ideas, Proposal No 269051 Italian Ministry of Education MIUR (FIRB prot. RBAP11ETKA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.