Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer

Thymidylate synthase (TS) is an important target for chemotherapy drugs suc h as 5-fluorouracil and raltitrexed. Over-expression of TS has been linked to chemotherapy resistance. A polymorphic tandem repeat sequence in the 5 ' untranslated region (5 ' UTR) of the human TS gene (TSER) has been shown t o influence TS expression. The presence of a triple tandem repeat (TSER*3) increases in vitro TS expression compared to a double tandem repeat (TSER*2 ) and is associated with higher in vivo tumor TS activity. The polymorphism of this promoter enhancer region has not been extensively studied in patie nts with cancer and may represent a possible mechanism of intrinsic resista nce to TS inhibitors. in this study, PCR analysis of genomic DNA from 121 p atients with colorectal cancer demonstrated 29% of patients were homozygous for TSER*3, 16% were homozygous for TSER*2 and 55% were heterozygous. In 4 4/45 microdissected tumors the TS enhancer genotype was identical between p aired samples of colorectal tumor and normal tissue. In 24 patients receivi ng a bolus/infusion 5-fluorouracil (5FU) regimen for metastatic colorectal cancer, 22% of non-responders to chemotherapy were homozygous for TSER*2 co mpared with 40% of responders. Median survival dropped from 16 months for h omozygous TSER*2 to 12 months for homozygous TSER*3. This is consistent wit h previous studies where higher TS expression was associated with poor resp onse to TS inhibitors. Prospective analysis of the influence of the TS poly morphism on patient outcome is warranted.