Genetic variation and haplotype structures of the gene encoding human thymidylate synthase, a pharmacogenetic marker in fluoropyrimidine-treated cancer patients

Abstract

14518 Background: Thymidylate synthase (TS) activity is an important determinant of response to chemotherapy with fluoropyrimidine prodrugs and its expression is largely determined by polymorphic features in the 5’ UTR region of the TS gene that can modify the number of the functional USF protein binding sites. Methods: DNA was extracted from peripheral blood from 587 caucasian cancer patients. Genotyping was performed by PCR amplification of the repeat region followed by automated sequencing Results: See Table. Conclusions: We define the genotypes of the 5’UTR region of the TS gene in a large cohort of caucasian cancer patients and we determine the number of functional USF binding sites that can be used as a pharmacogenetic marker in patients treated with fluoropyrimidines. The recently described 2RCC allele was also found in 6 patients, in all cases in heterozygous form. We identify a novel allele containing a 4bp insertion (cgcc) in the inverted repeat sequence located 2bp prior to the ATG start codon. In bold: novel allele. # Functional USF binding sites Genotypes* Colorectal cancer N (%) Breast cancer N (%) 1 2RGC/2RCC 0(0.0) 1(0.6) 2RCC/3RGCC 3(0.7) 0(0.0) 2 2RGC/2RGC 75(17.8) 40(24.1) 3RGCC/3RGCC 44(10.6) 13(7.8) 2RGC/3RGCC 103(24.5) 45(27.1) 2RCC/3RGGC 2(0.5) 0(0.0) 2RGC/3RGCC+ins6pb 4(1.0) 1(0.6) 3RGCC/3RGCC+ins6bp 3(0.7) 2(1.2) 3 3RGGC/3RGCC 75(17.8) 25(15.1) 2RGC/3RGGC 73(17.3) 27(16.3) 2RGC+ins4bp/3RGGC 1(0.2) 0(0.0) 3RGGC/3RGCC+ins6bp 3(0.7) 0(0.0) 4 3RGGC/3RGGC 32(7.6) 12(7.2) 2RGG/3RGGC 1(0.2) 0(0.0) 2RGC/4RGGGC 1(0.2) 0(0.0) 3RGGC/4RGGCC 1(0.2) 0(0.0) Total N: 421 Total N: 166 * According to Lincz et al. Int. J. Cancer 2007; 120:1930–34. No significant financial relationships to disclose.