Association between Polymorphisms of Thymidylate Synthase Gene and Clinical Outcome in Patients with Metastatic Colorectal Cancer Treated with 5-Fluorouracil-Based Chemotherapy

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths for population in Taiwan. Approximately 50% of patient with CRC have metastases (Stage III and IV) at the time of diagnosis and half of them are treated with chemotherapy. 5-fluorouracil (5-FU) has been the mainstay of CRC therapy for over 40 years. However, individual response and associated side effects to these drugs are often variable. The cytotoxic effect of 5-FU is mediated by the inhibition of thymidylate synthase (TS). Efficacy of 5-FU may therefore depend on the TS activity. Low TS expression in tumor has been shown to predict for better overall survival of 5-FU treatment in CRC. Expression of TS is determined largely by polymorphisms in the 5’- or 3’-untranslated region (UTR) of the human TS gene (TYMS) that influence its transcriptional and translational activity. This project will conduct an in vivo study to establish the relationship between TYMS polymorphisms and TS expression levels in the first year. A retrospective study will be used to investigate possible associations between TYMS polymorphisms and clinical outcome in the second year. In the last year, these associations will be validated by a prospective study. The specific aims are to: 1. detect novel single nucleotide polymorphisms (SNPs) or variations in the TYMS; 2. estimate the genotype and haplotype frequencies of TYMS; 3. determine the functional effects of the genotype and haplotype on the TS mRNA or protein expression levels; 4. investigate the associations between TYMS polymorphisms and TS activity on the clinical outcome in patients with metastatic CRC treated with 5-FU-based chemotherapy; To our best knowledge, this study will be the first to investigate the association between TYMS polymorphism and efficacy of 5-FU-based chemotherapy, as well as comprehensive sequencing analysis on TYMS in Chinese population. We anticipate innovative findings in the chemotherapy of CRC for population in Taiwan.