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Prognostic implications of thymidylate synthase gene polymorphisms in patients with advanced small bowel adenocarcinoma treated with first-line fluoropyrimidine-based chemotherapy.

Abstract
Thymidylate synthase (TS) gene polymorphisms such as tandem repeat (TR) polymorphisms and single-nucleotide polymorphisms (SNPs) affect transcriptional efficiency of the TS gene and may be prognostic markers for fluoropyrimidine-based therapy in various gastrointestinal cancers. However, data for TS polymorphisms on clinical outcomes in advanced small bowel adenocarcinoma (SBA) are limited. We retrospectively enrolled 58 locally advanced/metastatic SBA patients treated with first-line fluoropyrimidine-based chemotherapy and analyzed the relationship between TS genotypes and clinical outcomes in 30 patients who were available for tumor tissue. Based on TR polymorphisms and a G>C SNP in the promoter region of the TS gene, 74% of patients had high TS expression genotypes (2R/3RG, 3RG/3RC, 3RG/3RG); the remainder had low TS expression genotypes (2R/2R, 2R/3RC, 3RC/3RC). After a median follow-up of 48.8 months, median progression-free survival (PFS) and overall survival (OS) in all patients were 6.0 and 11.3 months, respectively. However, patients with low TS expression genotypes had better median PFS (12.8 vs. 4.3 months, P=0.027) and OS (28.8 vs. 8.9 months, P=0.025) than those with high TS expression genotypes. In multivariate analysis, poor Eastern Cooperative Oncology Group performance status [hazard ratio (HR), 2.85; 95% CI, 1.02-7.93] and high TS expression genotypes (HR, 3.49; 95% CI, 1.13-10.78) were independent prognostic factors for worse OS. Therefore, TS genotypes, based on a G>C SNP in the TR sequence of the TS gene, may be a useful biomarker for predicting outcomes for fluoropyrimidine-based chemotherapy in patients with locally advanced/metastatic SBA.
AuthorsHo-Young Yhim, Sang-Hee Cho, Sam Yong Kim, In Sung Cho, Kyu Taek Lee, Won Sup Lee, Soon Il Lee, Moo Rim Park, Sang-Gon Park, Hye-Suk Han, Yoon Seok Choi, Ik-Joo Chung, Hyun-Jeong Shim, Na-Ri Lee, Eun-Kee Song, Hee Sun Kim, Chang-Yeol Yim
JournalOncology reports (Oncol Rep) Vol. 34 Issue 1 Pg. 155-64 (Jul 2015) ISSN: 1791-2431 [Electronic] Greece
PMID25955097 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Thymidylate Synthase
  • Fluorouracil
Topics
  • Adenocarcinoma (drug therapy, genetics, pathology)
  • Adult
  • Aged
  • Aged, 80 and over
  • Disease-Free Survival
  • Duodenal Neoplasms (drug therapy, genetics, pathology)
  • Female
  • Fluorouracil (administration & dosage)
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide (genetics)
  • Prognosis
  • Tandem Repeat Sequences (genetics)
  • Thymidylate Synthase (genetics)
  • Treatment Outcome

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