Ko Kwang Hyun, Kim Nam Keun, Yim Dong Jin, Hong Sung Pyo, Park Pil Won, Rim Kyu Sung, Kim Sehyun, Hwang Seong Gyu
Department of Internal Medicine, College of Medicine, Pochon CHA University, Seongnam, South Korea.
Anticancer Res. 2006 Nov-Dec;26(6B):4229-33.
5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation; thymidylate synthase (TS) is a rate-limiting enzyme in the synthesis of dTMP and DNA repair. The clinical role of genetic polymorphisms of MTHFR and that of the TS enhancer region (TSER) were demonstrated in several clinical studies with colorectal, esophageal, gastric and breast cancer. However, there have never been any studies on the association between cholangiocarcinoma (CCC) and genetic polymorphisms of MTHFR and TSER. Therefore, the polymorphism of MTHFR and TSER, which share a common substrate, 5,10-methylenetetrahydrofolate, in CCC was examined, concurrently. The influence of these polymorphisms on plasma homocysteine levels was also investigated.
Blood samples were obtained from 47 patients with CCC and 204 healthy control donors. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), the C to T transition at position 677 of MTHFR and tandem repeat of 28bp in the enhancer region of TS gene were analyzed. Plasma homocysteine levels were also determined.
According to the logistic regression model, a combination of MTHFR 677CC with the TSER 2R(+) genotype had a relative risk of 5.38 (95% CI, 1.23-23.56) of developing CCC compared to MTHFR 677CC with TSER 2R(-) (p = 0.0257). The level of homocysteine was lower in CCC patients than healthy controls without statistical significance (8.27 +/- 4.17 vs. 9.40 +/- 2.57, p = 0.093).
Our data suggest a role of MTHFR 677CC with the TSER 2R(+) genotype in increasing the risk of CCC. This study is the first to suggest an association between CCC and the polymorphisms of MTHFR and TSER.
5,10-亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢中的关键酶，在为DNA甲基化提供甲基基团方面发挥主要作用；胸苷酸合成酶（TS）是dTMP合成和DNA修复中的限速酶。MTHFR基因多态性以及TS增强子区域（TSER）的临床作用已在多项针对结直肠癌、食管癌、胃癌和乳腺癌的临床研究中得到证实。然而，从未有过关于胆管癌（CCC）与MTHFR和TSER基因多态性之间关联的研究。因此，本研究同时检测了CCC中共享共同底物5,10-亚甲基四氢叶酸的MTHFR和TSER的多态性。还研究了这些多态性对血浆同型半胱氨酸水平的影响。
采集了47例CCC患者和204例健康对照者的血样。使用聚合酶链反应和限制性片段长度多态性（PCR-RFLP）分析MTHFR第677位的C到T转换以及TS基因增强子区域28bp的串联重复序列。同时测定血浆同型半胱氨酸水平。
根据逻辑回归模型，与MTHFR 677CC伴TSER 2R（-）相比，MTHFR 677CC伴TSER 2R（+）基因型发生CCC的相对风险为5.38（95%CI，1.23 - 23.56）（p = 0.0257）。CCC患者的同型半胱氨酸水平低于健康对照者，但无统计学意义（8.27±4.17 vs. 9.40±2.57，p = 0.093）。
我们的数据表明MTHFR 677CC伴TSER 2R（+）基因型在增加CCC风险中起作用。本研究首次提示CCC与MTHFR和TSER的多态性之间存在关联。
