Abstract 33: Thymidylate synthase polymorphisms and colorectal cancer risk and prognosis.
Authors: Buck Katharina , Beyerle Jolantha , Scherer Dominique , Habermann Nina , Paskow Michael J. , Pfuetze Katrin , Richter Swantje , Seibold Petra , Jansen Lina , Butterbach Katja , Burwinkel Barbara , Hoffmeister Michael , Benner Axel , Chang-Claude Jenny , Brenner Hermann , Koch Moritz , Weitz Juergen , Ulrich Cornelia M. 
Published: August 2013

Background: Thymidylate synthase (TS) is a key enzyme in folate metabolism and crucial for DNA synthesis and repair. Moreover, TS is an important target for chemotherapeutic drugs, such as 5-fluorouracil (5-FU) - a universal chemotherapeutic drug used for the treatment of colorectal cancer (CRC). TS over-expression may result in resistance to chemotherapy and may thus be a promising biomarker for therapeutic success. Previous studies revealed that at least three polymorphisms in the 5'- and 3'-untranslated regions (UTR) of the TS gene are associated with altered gene expression of TS coupled with a poor response to 5-FU treatment in CRC patients.

Methods: Eight tagSNPs in the TS gene as well as one insertion/deletion polymorphism located in the 3'-UTR of the gene were investigated for association with risk of CRC in 1,754 cases and 1,781 controls, and with overall survival (OS) and disease-specific survival (DSS) in 1,739 CRC cases of the German DACHS study. Patients were aged 30 years or older and diagnosed between 2003 and 2007. Associations were assessed using multiple logistic and Cox regression models.

Results: After a median follow-up time of 4.1 years, of the 442 deceased patients, 324 died due to CRC. There was no association between any polymorphism and CRC risk. Individuals with the heterozygote (het), but not with the rare homozygote variant (hzv) genotype of the rs495139 polymorphism (intronic region) had a significantly increased risk for overall (HRhet=1.63, 95% confidence interval (CI)=1.29-1.74 and HRhzv=1.28, 95% CI=0.94-1.74) and disease-specific mortality (HRhet=1.65, 95% CI=1.25-2.18 and HRhzv=1.11, 95% CI=0.76-1.60). No other polymorphism was associated with OS or DSS. However, several polymorphisms were associated with CRC risk when analyses were stratified by non-steroidal anti-inflammatory drug (NSAID) use. Also, several polymorphisms were associated with OS when analyses were stratified by 5-FU treatment, tumor stage, sex, and cancer site.

Conclusion: Genetic variation in the thymidylate synthase gene appears to be associated with CRC survival but not with CRC risk. Notably, effect modifications (which may be clinically relevant) were observed for several factors in the analysis of CRC risk and prognosis.

Citation Format: Katharina Buck, Jolantha Beyerle, Dominique Scherer, Nina Habermann, Michael J. Paskow, Katrin Pfuetze, Swantje Richter, Petra Seibold, Lina Jansen, Katja Butterbach, Barbara Burwinkel, Michael Hoffmeister, Axel Benner, Jenny Chang-Claude, Hermann Brenner, Moritz Koch, Juergen Weitz, Cornelia M. Ulrich. Thymidylate synthase polymorphisms and colorectal cancer risk and prognosis. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 33.