[Frontiers in Bioscience 16, 1036-1043, January 1, 2011]

TS gene tandem repeats in esophageal cancer patients receiving chemoradiotherapy

Kazuhiro Kaneko1,2, Maho Nagai2, Yoshitaka Murakami3, Mari Kogo4, Tsunehiro Oyama5, Takashi Kojima1, Atsushi Ohtsu1, Michio Imawari2

1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, 277-8577, Japan, 2Department of Gastroenterology, Showa University School of Medicine, Tokyo, 142-8666, Japan, 3Department of Health Science, Shiga University of Medical Science, Shiga, 520-2192, Japan, 4Promotion Center of Pharmaceutical Education, Showa University School of Pharmaceutical Sciences, Tokyo, 142-8666, Japan, 5Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and Methods
3.1. 3. Patients and Methods
3.1. Patient selection and sample collection
3.2. Treatment Schedule
3.3. Evaluation of Response
3.4. DNA extraction and determination of TR number in TS
3.5. Statistical Analysis
4. Results
4.1. Patient Characteristics
4.2. TR number in TS in control subjects and ESCC patients
4.3. TS TR variation and survival
5. Discussion
6. Acknowledgements
7. References

1. ABSTRACT

5-Fluorouracil (5-FU) interferes with tumor-cell proliferation by inhibiting thymidylate synthase (TS). We examined the relationship between tandem repeat (TR) variations in the TS gene and survival following concurrent chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC). TS-TR variations were analyzed in 57 stage II-IV ESCC patients undergoing chemoradiotherapy combined with 5-FU and cisplatinum (CDDP), and in 106 controls. Pretreatment non-neoplastic biopsy specimens from ESCC patients and lymphocytes from controls were used for analysis. Variations were identified by the size of DNA fragments amplified by polymerase chain reaction. Two to five TRs were found in Japanese individuals. TR3 homozygotes were predominant in 74% of ESCC patients and 61% of controls. Three-year survival rates were significantly longer in patients with TR2/2 or TR2/3 genotypes (38%) than in patients with TR3/3, 3/4, or 3/5 genotypes (9%; p=0.011). In the Cox proportional hazard model, the TR2/2 or TR2/3 genotypes were the only independent predictor for survival (Hazard ratio, 2.647; 95% confidence interval, 1.271-5.513). The TS-TR variations exert an important influence on survival following chemoradiotherapy in ESCC patients.