胸苷酸合成酶基因增强子区域的多态性与结直肠癌患者正常组织中的胸苷酸合成酶水平相关，但与恶性组织无关。

Polymorphisms in the enhancer region of the thymidylate synthase gene are associated with thymidylate synthase levels in normal tissues but not in malignant tissues of patients with colorectal cancer.

机构信息

Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

出版信息

Clin Colorectal Cancer. 2009 Jul;8(3):146-54. doi: 10.3816/CCC.2009.n.024.

DOI:10.3816/CCC.2009.n.024

PMID:19632929

Abstract

BACKGROUND

The enhancer region of the thymidylate synthase (TS) gene (TSER) contains a polymorphic tandem repeat sequence (2 or 3 repeats, 2R or 3R) and a single-nucleotide polymorphism (G > C) within the second repeat of the 3R alleles which might influence TS expression/activity and response to fluoropyrimidines. However, clinical studies in patients with colorectal cancer (CRC) failed to find a consistent relationship between TSER polymorphisms and protein levels as well as with clinical outcome. The analysis of the relationship between TSER genotype and TS mRNA and activity in normal and malignant tissues might explain the previous controversial data and help in the selection of useful markers to predict drug response and/or toxicity.

MATERIALS AND METHODS

To address this issue, we studied TSER genotype, TS expression, and activity with specific polymerase chain reaction and activity assays (TS catalytic activity and FdUMP binding) in normal (liver, mucosa) and malignant (primary tumor and liver metastasis) tissues from 83 patients with CRC.

RESULTS

No correlation between TSER genotype and TS mRNA and protein levels was observed in malignant tissues. In contrast, normal tissues harboring one or two 3RG alleles were characterized by higher TS protein levels (2.4-fold; P = .008) and catalytic activity (P < .05) compared with the other TSER genotypes.

CONCLUSION

These results suggest that TSER polymorphisms do not predict tumoral TS levels possibly depending on altered TS regulation in cancer tissues, and might explain the lack of clear correlation with clinical outcome after chemotherapy with fluoropyrimidines. However, the relationship between TS phenotype and TSER genotype in normal tissues warrants further investigations in large-scale prospective studies evaluating TS genotype and fluoropyrimidine tolerability.

摘要

背景

胸苷酸合成酶（TS）基因的增强子区域（TSER）包含一个多态性串联重复序列（2 或 3 个重复，2R 或 3R）和 3R 等位基因第二个重复内的单核苷酸多态性（G > C），这可能影响 TS 的表达/活性和对氟嘧啶的反应。然而，在结直肠癌（CRC）患者的临床研究中，未能发现 TSER 多态性与蛋白水平以及与临床结果之间存在一致的关系。分析 TSER 基因型与正常和恶性组织中 TS mRNA 和活性之间的关系，可能解释以前有争议的数据，并有助于选择有用的标记物来预测药物反应和/或毒性。