Agglomerative epigenetic aberrations are a common event in human breast cancer.
Agglomerative epigenetic aberrations are a common event in human breast cancer.
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DOI：
10.1158/0008-5472.can-08-1419
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Futscher BW
中科院分区：
文献类型：
--
作者：
Novak P;Jensen T;Oshiro MM;Watts GS;Kim CJ;Futscher BW
DNA甲基化模式的变化是癌细胞的共同特征。最近的研究表明，DNA甲基化不仅影响离散的基因，而且还可以影响大的染色体区域，可能导致长距离表观遗传沉默。目前尚不清楚这种长距离表观遗传事件在癌症中是否相对罕见或频繁发生。在这里，我们使用高分辨率的启动子平铺阵列方法来分析乳腺癌标本和正常乳腺组织中的DNA甲基化，以解决这个问题。我们在人乳腺癌中鉴定了3506个癌症特异性差异甲基化区域（DMR），其中2033个为高甲基化事件，1473个为低甲基化事件。这些DMR大多数在乳腺癌中复发; 90%的已识别DMR发生在至少33%的样本中。有趣的是，我们发现了整个基因组中异常甲基化区域的非随机空间分布，显示出集中在相对较小的基因组区域的趋势。这种高甲基化和低甲基化DMR的聚集体跨越多达数百个酶，并且经常在基因家族簇中发现。高甲基化事件通常发生在CpG岛启动子的转录起始位点附近，而低甲基化事件经常发生在片段重复区域。一个新发现的与乳腺癌基因沉默相关的高甲基化DMR聚集体的例子，我们更详细地研究了5号染色体上的原钙粘蛋白基因家族簇（PCDHA，PCDHB和PCDHG）。综上所述，我们的研究结果表明，聚集性表观遗传畸变是人类乳腺癌的常见事件。
Changes in DNA methylation patterns are a common characteristic of cancer cells. Recent studies suggest that DNA methylation affects not only discrete genes, but it can also affect large chromosomal regions, potentially leading to long range epigenetic silencing. It is unclear whether such long-range epigenetic events are relatively rare or frequent occurrences in cancer. Here we use a high-resolution promoter tiling array approach to analyze DNA methylation in breast cancer specimens and normal breast tissue to address this question. We identified 3506 cancer specific differentially methylated regions (DMR) in human breast cancer with 2033 being hypermethylation events and 1473 hypomethylation events. Most of these DMRs are recurrent in breast cancer; 90% of the identified DMRs occurred in at least 33% of the samples. Interestingly, we found a non-random spatial distribution of aberrantly methylated regions across the genome that showed a tendency to concentrate in relatively small genomic regions. Such agglomerates of hyper- and hypomethylated DMRs spanned up to several hundred kilobases and were frequently found at gene family clusters. The hypermethylation events usually occurred in the proximity of the transcription start site in CpG island promoters while hypomethylation events were frequently found in regions of segmental duplication. One example of a newly discovered agglomerate of hypermethylated DMRs associated with gene silencing in breast cancer that we examined in greater detail involved the protocadherin gene family clusters on chromosome 5 (PCDHA, PCDHB, and PCDHG). Taken together, our results suggest that agglomerative epigenetic aberrations are frequent events in human breast cancer.