Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels
Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels
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DOI：
10.1111/j.1349-7006.2009.01321.x
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发表时间：
2009-12-01
期刊：
影响因子：
5.7
通讯作者：
Minamoto, Toshinari
中科院分区：
文献类型：
--
作者：
Jin, MingJi;Kawakami, Kazuyuki;Minamoto, Toshinari
异常DNA甲基化是肺癌中一种常见的表观遗传改变。叶酸被认为在DNA甲基化的稳态中起作用，也与癌症化疗有关。我们通过测量72例非小细胞肺癌（NSCLC）患者肿瘤和邻近正常组织中的叶酸浓度，研究了叶酸在DNA甲基化中的可能作用。将这些数据与DNA甲基化水平和临床病理特征进行比较。叶酸浓度测定为5,10-亚甲基四氢叶酸和四氢叶酸的总和。MethyLight检测用于定量P16（CDKN2A）、APC、CDH13、RARB、RASSF1、RUNX3和MYOD1启动子区域的甲基化。LINE-1重复序列的甲基化被用作全局甲基化的替代。肿瘤中叶酸水平与LINE-1、CDH13和RUNX3甲基化呈正相关。与鳞状细胞癌（SCC）相比，腺癌中叶酸浓度和LINE-1、RASSF1和RUNX3的甲基化明显更高。从Gene Expression Omnibus检索到的两组基于阵列的数据一致显示，与鳞状细胞癌相比，腺癌中叶酸转运酶FOLR1和阻止叶酸保留的酶GGH的表达分别更高和更低。通过定量RT-PCR在26例腺癌和13例鳞状细胞癌中独立验证了这一点。我们的研究结果表明，叶酸代谢在非小细胞肺癌的异常DNA甲基化中起作用。这里观察到的叶酸浓度和DNA甲基化的组织学亚型差异与叶酸代谢酶的不同表达模式有关。这些发现可能对非小细胞肺癌的氟嘧啶和抗叶酸药物的组织学定向化疗具有临床应用价值。[j] .癌症科学，2009;100:2325-2330。
Aberrant DNA methylation is a commonly observed epigenetic change in lung cancer. Folate has been suggested to play a role in the homeostasis of DNA methylation and has also been implicated in cancer chemotherapy. We investigated a possible role for folate in DNA methylation by measuring folate concentrations in tumors and adjacent normal tissues from 72 non-small cell lung cancer (NSCLC) patients. These were compared to DNA methylation levels and to clinicopathological features. Folate concentrations were determined as the sum of 5,10-methylenetetrahydrofolate and tetrahydrofolate. The MethyLight assay was used to quantitate methylation in promoter regions of P16(CDKN2A), APC, CDH13, RARB, RASSF1, RUNX3, and MYOD1. Methylation of LINE-1 repeats was used as a surrogate for global methylation. Folate levels in tumors correlated positively with LINE-1, CDH13, and RUNX3 methylation. Folate concentrations and methylation of LINE-1, RASSF1, and RUNX3 were significantly higher in adenocarcinoma compared to squamous cell carcinoma (SCC). Two sets of array-based data retrieved from the Gene Expression Omnibus consistently showed that expression of FOLR1, a folate transport enzyme, and GGH, an enzyme that prevents folate retention, were higher and lower, respectively, in adenocarcinomas compared to SCC. This was independently validated by quantitative RT-PCR in 26 adenocarcinomas and 13 SCC. Our results suggest that folate metabolism plays a role in aberrant DNA methylation in NSCLC. The histological subtype differences in folate concentration and DNA methylation observed here were associated with distinct expression patterns for folate metabolizing enzymes. These findings may have clinical applications for histology-directed chemotherapy with fluoropyrimidine and anti-folates in NSCLC. (Cancer Sci 2009l; 100: 2325-2330).