Thymidylate synthase gene polymorphism affects the response to preoperative 5-fluorouracil chemoradiation therapy in patients with rectal cancer.

This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RC and 3RC/3RC were defined as the low-expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low-expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU-based CRT in rectal cancer.

Hur H ，Kang J ，Kim NK ，Min BS ，Lee KY ，Shin SJ ，Keum KC ，Choi J ，Kim H ，Choi SH ，Lee MY ... -  《-》

Polymorphic tandem repeat sequences of the thymidylate synthase gene correlates with cellular-based sensitivity to fluoropyrimidine antitumor agents.

Yawata A ，Kim SR ，Miyajima A ，Kubo T ，Ishida S ，Saito Y ，Nakajima Y ，Katori N ，Matsumoto Y ，Fukuoka M ，Ohno Y ，Ozawa S ，Sawada J ... -  《CANCER CHEMOTHERAPY AND PHARMACOLOGY》

X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients.

5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression. XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.

Lamas MJ ，Duran G ，Gomez A ，Balboa E ，Anido U ，Bernardez B ，Rana-Diez P ，Lopez R ，Carracedo A ，Barros F ... -  《-》

Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers.

Morganti M ，Ciantelli M ，Giglioni B ，Putignano AL ，Nobili S ，Papi L ，Landini I ，Napoli C ，Valanzano R ，Cianchi F ，Boddi V ，Tonelli F ，Cortesini C ，Mazzei T ，Genuardi M ，Mini E ... -  《EUROPEAN JOURNAL OF CANCER》

Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation.

Stoehlmacher J ，Goekkurt E ，Mogck U ，Aust DE ，Kramer M ，Baretton GB ，Liersch T ，Ehninger G ，Jakob C ... -  《-》