Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value
Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value
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DOI：
10.1038/ncomms6899
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发表时间：
2015-02-01
影响因子：
16.6
通讯作者：
Clark, Susan J.
中科院分区：
文献类型：
--
作者：
Stirzaker, Clare;Zotenko, Elena;Clark, Susan J.
癌症甲基化组的表观遗传改变在乳腺癌中很常见，并为肿瘤分层提供了新的选择。在这里，我们对从福尔马林固定的石蜡包埋组织中分离的少量DNA进行全基因组甲基化捕获测序，这些组织来自三阴性乳腺癌（TNBC）和匹配的正常样本。我们确定差异甲基化区域（DMR）丰富的启动子与转录因子结合位点和DNA超敏位点。重要的是，我们将TNBC分为三个不同的甲基化簇，这些甲基化簇与更好或更差的预后相关，并确定了17个与总生存率密切相关的DMR，包括位于Wilms肿瘤1（WT 1）基因、双向启动子和反义WT 1-AS的DMR。我们的数据显示，协调的超甲基化可以发生在雌激素受体阴性疾病，表征表观遗传框架提供了一个潜在的签名，以分层TNBC。总之，我们的研究结果证明了用有限的存档组织分析癌症甲基化组以鉴定与癌症相关的调控区域的可行性。
Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.