Saffroy Raphaël, Pham Patrick, Chiappini Franck, Gross-Goupil Marine, Castera Laurent, Azoulay Daniel, Barrier Alain, Samuel Didier, Debuire Brigitte, Lemoine Antoinette
Service de Biochimie et Biologie moléculaire, Cedex, France.
Carcinogenesis. 2004 Aug;25(8):1443-8. doi: 10.1093/carcin/bgh147. Epub 2004 Mar 19.
Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation and in the production of dTMP for DNA synthesis. Different polymorphisms have been described for this enzyme, the most studied being the C677T, which has been shown to be associated with predisposition to colorectal cancer in patients who consume a high alcohol diet. The aim of this study was to determine whether the MTHFR polymorphism is related to hepatocellular carcinoma (HCC) in patients with alcoholic cirrhosis. MTHFR genotypes were determined in 300 liver transplant patients, 72 of whom had alcoholic cirrhosis with HCC and 122 of whom had alcoholic cirrhosis without HCC. The remaining patients were transplanted for HCC on normal liver (n = 27) or viral cirrhosis with HCC (n = 49) or without HCC (n = 30). We also tested 80 healthy subjects. Among the group of patients transplanted for alcoholic cirrhosis, the frequency of MTHFR variants CC versus CT and TT was significantly higher in patients with HCC than in patients without macroscopic evidence of HCC (P = 0.02). This difference was not observed between patients with and without HCC developed either on viral cirrhosis or on non-cirrhotic liver. If we considered all the patients transplanted for HCC, the MTHFR CC genotype was significantly higher in patients who had developed HCC on alcoholic cirrhosis rather than on viral cirrhosis (P = 0.002) or on non-cirrhotic livers (P = 0.02). The relative risk for HCC in subjects with alcoholic cirrhosis and the CC genotype was 2.03. These results suggest that the MTHFR CC genotype increases the risk to develop HCC in patients who consume a high alcohol diet.
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以及为DNA合成产生脱氧胸苷一磷酸（dTMP）过程中发挥主要作用。已发现该酶存在不同的多态性，其中研究最多的是C677T，研究表明，在高酒精饮食的患者中，它与结直肠癌易感性有关。本研究的目的是确定MTHFR多态性是否与酒精性肝硬化患者的肝细胞癌（HCC）相关。对300例肝移植患者的MTHFR基因型进行了测定，其中72例为伴有HCC的酒精性肝硬化患者，122例为不伴有HCC的酒精性肝硬化患者。其余患者因正常肝脏的HCC（n = 27）、伴有HCC的病毒性肝硬化（n = 49）或不伴有HCC的病毒性肝硬化（n = 30）而接受移植。我们还检测了80名健康受试者。在因酒精性肝硬化接受移植的患者组中，伴有HCC的患者中MTHFR变异型CC与CT和TT的频率显著高于无肉眼可见HCC证据的患者（P = 0.02）。在病毒性肝硬化或非肝硬化肝脏上发生或未发生HCC的患者之间未观察到这种差异。如果我们考虑所有因HCC接受移植的患者，在酒精性肝硬化上发生HCC的患者中MTHFR CC基因型显著高于在病毒性肝硬化（P = 0.002）或非肝硬化肝脏（P = 0.02）上发生HCC的患者。酒精性肝硬化且具有CC基因型的受试者发生HCC的相对风险为2.03。这些结果表明，MTHFR CC基因型增加了高酒精饮食患者发生HCC的风险。
