Yegnasubramanian Srinivasan, Haffner Michael C, Zhang Yonggang, Gurel Bora, Cornish Toby C, Wu Zhijin, Irizarry Rafael A, Morgan James, Hicks Jessica, DeWeese Theodore L, Isaacs William B, Bova G Steven, De Marzo Angelo M, Nelson William G
Sidney Kimmel Comprehensive Cancer Center, School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Cancer Res. 2008 Nov 1;68(21):8954-67. doi: 10.1158/0008-5472.CAN-07-6088.
Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in (5me)C content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisulfite genomic sequencing-based approach to identify genes that are silenced by CpG island methylation in normal prostate cells but become overexpressed in prostate cancer cells as a result of CpG island hypomethylation. Through this analysis, we show that a class of cancer testis antigen genes undergoes CpG island hypomethylation and overexpression in primary prostate cancers, but more so in metastatic prostate cancers. Finally, we show that DNA hypomethylation patterns are quite heterogeneous across different metastatic sites within the same patients. These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination.
基因组DNA中CpG二核苷酸的低甲基化是在人类癌症中发现的最早的体细胞表观遗传改变之一。据推测，DNA低甲基化几乎在所有人类癌症的早期就会发生，可能会促进基因不稳定以及癌症的起始和进展。因此，我们研究了人类前列腺癌中DNA低甲基化变化的性质、程度和时间。与普遍认为的全球DNA低甲基化变化在所有人类癌症的极早期就会发生的观点相反，我们发现基因组中（5me）C含量的降低在前列腺癌进展过程中出现得非常晚，仅在转移性疾病阶段才会在显著程度上出现。此外，我们发现，虽然与正常组织相比，原发性前列腺癌中确实存在一些LINE1启动子低甲基化，但这种LINE1低甲基化在转移性前列腺癌中更为明显。接下来，我们采用了分层基因表达微阵列和基于亚硫酸氢盐基因组测序的方法，以鉴定在正常前列腺细胞中因CpG岛甲基化而沉默，但在前列腺癌细胞中由于CpG岛低甲基化而过度表达的基因。通过这项分析，我们表明一类癌症睾丸抗原基因在原发性前列腺癌中经历了CpG岛低甲基化和过度表达，但在转移性前列腺癌中更为明显。最后，我们表明同一患者不同转移部位的DNA低甲基化模式差异很大。这些发现提供了证据，表明DNA低甲基化变化在前列腺癌发生过程中比CpG岛高甲基化变化出现得更晚，并且在前列腺癌进展和转移扩散过程中呈现异质性。
