Normal cell-type epigenetics and breast cancer classification: a case study of cell mixture-adjusted analysis of DNA methylation data from tumors.
Normal cell-type epigenetics and breast cancer classification: a case study of cell mixture-adjusted analysis of DNA methylation data from tumors.
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DOI：
10.4137/cin.s13980
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发表时间：
2014
影响因子：
2
通讯作者：
Ince TA
中科院分区：
文献类型：
--
作者：
Houseman EA;Ince TA
从历史上看，乳腺癌分类依赖于预后亚型。因此，与造血系统癌症不同，乳腺肿瘤分类缺乏系统发生学原理。近年来，基于雌激素受体（ER）、雄激素受体（AR）、维生素D受体（VDR）和角蛋白5（Keratin 5）表达的乳腺肿瘤系统发育分类的可行性已得到证实。已经提出了四种激素状态（HR 0 -3），包括乳腺细胞的11种细胞亚型。该分类方案已被证明与临床预后相关。我们研究的影响，这种系统发育分类的DNA甲基化的乳腺肿瘤和正常乳腺组织应用最近开发的去卷积算法的基因表达综合存档的三个DNA甲基化数据集。我们认为，乳腺肿瘤起源于一个特定的细胞，基本上放大了其原始细胞类型的表观遗传状态。我们证明，肿瘤的DNA甲基化表现出与细胞特异性表观遗传状态一致的模式，这些状态大致对应于之前假设的正常乳腺细胞类型，并且对潜在细胞类型比例的估计可以预测肿瘤表型。总之，这些发现表明乳腺肿瘤的表观遗传学最终是基于正常乳腺组织的潜在遗传学。
Historically, breast cancer classification has relied on prognostic subtypes. Thus, unlike hematopoietic cancers, breast tumor classification lacks phylogenetic rationale. The feasibility of phylogenetic classification of breast tumors has recently been demonstrated based on estrogen receptor (ER), androgen receptor (AR), vitamin D receptor (VDR) and Keratin 5 expression. Four hormonal states (HR0–3) comprising 11 cellular subtypes of breast cells have been proposed. This classification scheme has been shown to have relevance to clinical prognosis. We examine the implications of such phylogenetic classification on DNA methylation of both breast tumors and normal breast tissues by applying recently developed deconvolution algorithms to three DNA methylation data sets archived on Gene Expression Omnibus. We propose that breast tumors arising from a particular cell-of-origin essentially magnify the epigenetic state of their original cell type. We demonstrate that DNA methylation of tumors manifests patterns consistent with cell-specific epigenetic states, that these states correspond roughly to previously posited normal breast cell types, and that estimates of proportions of the underlying cell types are predictive of tumor phenotypes. Taken together, these findings suggest that the epigenetics of breast tumors is ultimately based on the underlying phylogeny of normal breast tissue.