DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases.
DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases.
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DOI：
10.1126/scitranslmed.3005211
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发表时间：
2013-01-23
影响因子：
17.1
通讯作者：
Yegnasubramanian S
中科院分区：
文献类型：
--
作者：
Aryee MJ;Liu W;Engelmann JC;Nuhn P;Gurel M;Haffner MC;Esopi D;Irizarry RA;Getzenberg RH;Nelson WG;Luo J;Xu J;Isaacs WB;Bova GS;Yegnasubramanian S
人类癌症几乎普遍存在表观遗传改变。虽然表观遗传标记的这种改变，包括DNA甲基化，是潜在的遗传，但它们也可以动态改变。鉴于这种可塑性的潜力，表观遗传变化在多大程度上可以受到选择和作为肿瘤形成的驱动因素一直受到质疑。在这里，我们对致命的转移性前列腺癌中的DNA甲基化改变进行了基因组规模的分析，并创建了DNA甲基化“城市景观”图来可视化这些复杂的数据。我们发现，体细胞DNA甲基化改变，尽管显示出显着的个体间异质性之间的男性致命的转移性前列腺癌，保持在同一个人的所有转移。DNA甲基化改变的总体维持程度与遗传拷贝数改变的维持程度相当。个体间频繁高甲基化的区域明显富集癌症和发育/分化相关基因。此外，个体内转移灶之间表现出高度一致性的高甲基化的区域，即使个体之间存在高甲基化，也显示出癌症相关基因的富集。有趣的是，尽管一些区域在启动子甲基化中显示出个体内转移性肿瘤异质性，但这种甲基化改变通常与基因表达无关。这是尽管启动子甲基化模式与基因表达强烈相关的一般趋势，特别是在个体间甲基化的区域。这些发现表明，DNA甲基化改变有可能在致癌和疾病进展中产生可选择的驱动事件，并突出了靶向这种表观基因组改变以开发纵向标记和治疗策略的可能性。
Human cancers nearly ubiquitously harbor epigenetic alterations. While such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. Here, we carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation “cityscape” plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked inter-individual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer and development/differentiation related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment of cancer-related genes. Interestingly, whereas some regions showed intra-individual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP
影响因子：
21.3
作者：
Coolen, Marcel W.;Stirzaker, Clare;Song, Jenny Z.;Statham, Aaron L.;Kassir, Zena;Moreno, Carlos S.;Young, Andrew N.;Varma, Vijay;Speed, Terence P.;Cowley, Mark;Lacaze, Paul;Kaplan, Warren;Robinson, Mark D.;Clark, Susan J.
通讯作者：
Clark, Susan J.
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.