The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.
The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.
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DOI：
10.1002/ijc.24003
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发表时间：
2009-05-01
影响因子：
6.4
通讯作者：
Kim, Young-In
中科院分区：
文献类型：
--
作者：
Sohn, Kyoung-Jin;Jang, Hyeran;Campan, Mihaela;Weisenberger, Daniel J.;Dickhout, Jeffrey;Wang, Yi-Cheng;Cho, Robert C.;Yates, Zoe;Lucock, Mark;Chiang, En-Pei;Austin, Richard C.;Choi, Sang-Woon;Laird, Peter W.;Kim, Young-In
亚甲基四氢叶酸还原酶（MTHFR）基因C677 T多态性与结肠癌风险降低相关，但可能增加乳腺癌风险。这种多态性与细胞内叶酸辅因子的变化有关，这可能通过改变一碳转移反应影响DNA甲基化和合成。我们研究了这种突变对DNA甲基化和尿嘧啶错误掺入的影响及其与外源性叶酸的相互作用，以进一步调节HCT 116结肠癌和MDA-MB-435乳腺癌细胞中MTHFR 677 T突变体外模型中的这些一碳转移反应的生物标志物。在HCT 116细胞中，当叶酸供应充足或高时，MTHFR 677 T突变与基因组DNA甲基化显著增加相关;然而，在叶酸不足的情况下，该突变与基因组DNA甲基化显著降低相关。相比之下，在MDA-MB-435细胞中，当叶酸供应充足或高时，MTHFR 677 T突变与基因组DNA甲基化显著降低相关，而当叶酸供应低时，MTHFR 677 T突变无影响。MTHFR 677 T突变分别与HCT 116和MDA-MB-435细胞中尿嘧啶错误掺入减少和增加的非显著趋势相关。我们的数据首次证明了MTHFR 677 T突变引起的细胞内叶酸辅因子变化的功能性后果，从而提供了一种合理的细胞机制，可以部分解释与MTHFR C677 T突变相关的结肠癌和乳腺癌风险的位点特异性修饰。
The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer while it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one-carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one-carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA-MB-435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA-MB-435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA-MB-435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site-specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation.
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影响因子：
3.5
作者：
Chen, ZT;Karaplis, AC;Rozen, R
通讯作者：
Rozen, R
影响因子：
4.2
作者：
Choi, SW;Mason, JB
通讯作者：
Mason, JB
DOI：
10.1073/pnas.062066299
发表时间：
2002-04-16
影响因子：
11.1
作者：
Friso, S;Choi, SW;Selhub, J
通讯作者：
Selhub, J
影响因子：
4.3
作者：
Batra, Vipen;Mishra, Kaushala P.
通讯作者：
Mishra, Kaushala P.
影响因子：
4.2
作者：
Hayashi, Inki;Sohn, Kyoung-Jin;Kim, Young-In
通讯作者：
Kim, Young-In