Fourteen Novel Genetic Variations and Haplotype Structures of the TYMS Gene Encoding Human Thymidylate Synthase (TS)

Summary:Forty genetic variations including 14 novel ones were found in the human TYMS gene, which encodes thymidylate synthase, in 263 Japanese cancer patients who received 5-fluorouracil (FU)-based chemotherapy. Three novel variations were located within the 28-bp tandem repeat sequence in the 5'-untranslated region (UTR) and were designated 5Rc, 3Rc-ins and 4Rc. Allele frequencies were 0.021 for 5Rc, 0.006 for 3Rc-ins and 0.002 for 4Rc. Other novel variations included –133G>C and –125G>C in the 5'-UTR; IVS1–278G>A, IVS2–68C>T, IVS2–23T>C, IVS4 + 122_ + 123in-sATTG, IVS4–141G>A, IVS5–100A>T and IVS6–111G>A in the introns; and 1244(*302)A>G and 1264(*322)G > A in the 3'-UTR. The allele frequencies were 0.34 for IVS4 + 122_ + 123insATTG, 0.042 for –133G>C, 0.011 for IVS4–141G > A, 0.006 for –125G>C, 0.004 for IVS1–278G>A, IVS2 –68C>T, 1244(*302)A>G and 1264(*322)G>A, and 0.002 for IVS2–23T>C, IVS5–100A>T and IVS6–111G>A. Using the detected polymorphisms, linkage disequilibrium (LD) analysis was performed, which divided the TYMS gene into three LD blocks. The 28-bp tandem repeat sequence in the 5'-UTR was assigned as Block 2 with a total of 7 alleles. In Blocks 1 and 3, 7 and 19 haplotypes were determined /inferred, respectively. Our findings provide fundamental and useful information for genotyping TYMS in the Japanese and probably other Asian populations.