DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis.
DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis.
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DOI：
10.1371/journal.pone.0027889
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Issa JP
中科院分区：
文献类型：
--
作者：
Konishi K;Watanabe Y;Shen L;Guo Y;Castoro RJ;Kondo K;Chung W;Ahmed S;Jelinek J;Boumber YA;Estecio MR;Maegawa S;Kondo Y;Itoh F;Imawari M;Hamilton SR;Issa JP
DNA甲基化在结直肠癌（CRC）转移过程中的作用尚不清楚。我们采用亚硫酸氢盐焦磷酸测序法检测了79例CRC中13个基因（MINT 1、MINT 2、MINT 31、MLH 1、p16、p14、TIMP 3、CDH 1、CDH 13、THBS 1、MGMT、HPP 1和ERα）的甲基化状态，其中包括36例无肝转移的CRC和43例有肝转移的CRC，包括16对原发性CRC和肝转移。我们还在三对原发性和转移性癌症中进行了甲基化CpG岛扩增微阵列（MCAM）。原发性CRC中p14、TIMP 3和HPP 1的甲基化从无肝转移到有肝转移逐渐降低（分别为13.1% vs.4.3%; 14.8% vs.3.7%; 43.9% vs.35.8%）（P<0.05）。当配对的原发性和转移性肿瘤进行比较时，只有MGMT甲基化在转移性癌症中显著更高（27.4%对13.4%，P = 0.013），这种差异是由于大多数病例中甲基化密度而不是频率的增加。 MCAM显示转移性样本中DNA甲基化基因平均增加7.4%。肝转移瘤中差异性高甲基化基因的数量随着原发灶切除和肝转移瘤切除之间时间的增加而增加。在12个配对样本中的亚硫酸氢盐焦磷酸测序验证表明，这些增加中的大多数是不保守的，并且可以通过甲基化密度而不是频率的差异来解释。原发性CRC和匹配的肝转移瘤之间的大多数DNA甲基化差异是由于随机变异和DNA甲基化密度的增加，而不是从头失活和沉默。因此，DNA甲基化变化大部分发生在进展为肝转移之前。
The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear. We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers. Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency. Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis.
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