Loss of Heterozygosity at the Thymidylate Synthase ( TS ) Locus on Chromosome 18 Affects Tumor Response and Survival in Individuals Heterozygous for a 28-bp Polymorphism in the TS Gene

Abstract

Thymidylate synthase (TS), the target enzyme of the fluoropyrimidine class of drugs, has a 28-bp repeat polymorphism in the promoter region that has been associated with response of tumors to 5-fluorouracil-based therapy. Patients homozygous for the double repeat (2R/2R) in the TS gene have an overall better outcome from treatment than patients homozygous for the triple repeat (3R/3R). However, due to loss of heterozygosity at the TS locus on chromosome 18 in cancer cells, heterozygous 2R/3R individuals can acquire the 2R/loss or the 3R/loss genotype in their tumors. The purpose of this study was to determine whether the response of colorectal cancer to fluoropyrimidine therapy is associated with the resulting tumor TS genotype when loss of heterozygosity occurs in tumor DNA. A total of 30 colorectal cancer patients treated with the fluoropyrimidinebased combination S-1, all of whom had stage IV disease, were studied. The response rate to S-1 in this group of patients was 13 of 30 (43%). The heterozygous 2R/3R genotype was found in 22 of 30 normal tissues, whereas 10 (45%) of the matched cancer tissues showed only the 2R-sequence band (2R/loss), and 7 cancer tissues (32%) showed only the 3R-sequence band (3R/loss). The response rate of the 2R/loss tumor genotype patients was 80% (8 of 10) compared with 14% (1 of 7) in the 3R/loss genotype group (P ‫؍‬ 0.029). Patients with tumor 3R/loss genotypes had significantly lower survival than 2R/loss genotypes. Heterozygous patients with a 2R/loss tumor genotype had the same survival as 2R/2R patients, whereas patients with a 2R/3R tumor genotype had a short survival similar to homozygous 3R/3R genotypes. These results show that: (a) response to 5-fluorouracil-based therapy is determined by tumor genotype; and (b) the 3R repeat is a direct negative determinant of outcome.

The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

“…On the other hand, a recent study indicated that determination of genetic polymorphisms in peripheral blood may not be representative for the situation in tumour tissue. Thus, Uchida et al (2004) have shown that individuals heterozygous for the 28-bp polymorphism in the TS gene may have cancers that are homozygous for this polymorphism due to loss of one allele during carcinogenesis. Furthermore, they could show that the response to 5-FU-based chemotherapy in these cases was comparable to cases where the entire individual was homozygous.…”

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…In a small study of 30 stage IV colorectal cancer patients, LOH was observed in 17 out of 22 heterozygotes. 38 The presence of a TSER*3 allele (homozygous TSER*3, heterozygous and TSER*3/loss) was associated with lower survival on fluoropyrimidine chemotherapy. LOH in tumour tissue is a significant factor, to be taken into account when TS genotypes are to be considered for outcome prediction.…”

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

“…Patients with *2/*2 genotype have a good prognosis, but patients with *3/*2 genotype are sometimes included in the good prognosis group 27 and other times in the intermediate or bad prognosis group. 12,26 In a recent work, Uchida et al 29 reported that the loss of heterozygosity at the TS locus in tumor samples of colorectal cancer patients treated with fluoropyrimidine therapy affects tumor response and survival in those patients with a heterozygous TS*2/*3 genotype. In 17 of 22 of these heterozygous cases, a LOH was demonstrated in tumor tissues The authors reported that the response rate of the TS*2/loss tumor genotype patients was 80% and that only 1 of 7 tumors with a genotype of *3/loss showed a response.…”