Plaschke Jens, Schwanebeck Uta, Pistorius Steffen, Saeger Hans D, Schackert Hans K
Department of Surgical Research, Carl Gustav Carus Hospital, Dresden University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany.
Cancer Lett. 2003 Mar 10;191(2):179-85. doi: 10.1016/s0304-3835(02)00633-x.
Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic (n = 227) or suspected/verified hereditary disease (n = 60) and tumours exhibiting high-level microsatellite instability (n = 41) or not (n = 246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA + AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A --> C variant.
亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢中的一种关键酶，它影响DNA合成和甲基化。酶活性降低可能会减少DNA甲基化能力，并可能减少尿嘧啶错误掺入DNA，进而导致双链断裂。这两个过程可能对人类细胞的致癌转化至关重要。MTHFR中已发现两种常见的导致氨基酸改变且酶活性降低的核苷酸多态性（677C→T/Ala222Val和1298A→C/Glu428Ala）。我们对287例结直肠癌患者的样本与346例健康对照样本中这两种多态性相关的相对风险进行了评估。还进一步确定了散发性（n = 227）或疑似/确诊遗传性疾病（n = 60）以及表现出高微卫星不稳定性（n = 41）或未表现出高微卫星不稳定性（n = 246）的癌症患者亚组的相对风险。在所分析的队列中，单独或联合考虑MTHFR基因型时，未观察到结直肠癌相对风险的显著差异，尽管在60例遗传性疾病患者中1298AA + AC基因型的频率有所增加。虽然我们的结果总体上不支持高酶活性与结直肠癌风险增加之间存在关联，但我们不能排除遗传性疾病患者与MTHFR 1298A→C变异之间存在关联。
