DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.
DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.
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DOI：
10.1038/s41467-021-25661-w
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发表时间：
2021-09-13
影响因子：
16.6
通讯作者：
Caldas C
中科院分区：
文献类型：
--
作者：
Batra RN;Lifshitz A;Vidakovic AT;Chin SF;Sati-Batra A;Sammut SJ;Provenzano E;Ali HR;Dariush A;Bruna A;Murphy L;Purushotham A;Ellis I;Green A;Garrett-Bakelman FE;Mason C;Melnick A;Aparicio SAJR;Rueda OM;Tanay A;Caldas C
DNA甲基化在癌症中是异常的，但这种表观遗传变化的动态、调节作用和临床意义仍然知之甚少。在这里，来自METABRIC队列的1538个乳腺肿瘤和244个正常乳腺组织的简化代表性亚硫酸盐测序(RRBS)谱被报道，促进了在丰富的基因组、转录和临床数据的背景下对DNA甲基化的详细分析。来自免疫和间质信号的肿瘤甲基化被去卷曲，导致在非CpG岛上发现了具有全基因组甲基化缺失的肿瘤复制相关时钟。出乎意料的是，大多数肿瘤CpG岛的甲基化遵循两个复制无关的获得(MG)或丢失(ML)过程，我们称之为表观基因组不稳定性。表观基因组不稳定性与肿瘤分级、分期、TP53突变及预后不良有关。在控制了这些全球反式作用趋势以及X连锁剂量补偿效应后，在数百个启动子和1000多个远端元件中发现了顺式特异性甲基化和表达相关性。其中一些针对已知的肿瘤抑制基因和癌基因。总之，这项研究表明，全球表观遗传不稳定性可以侵蚀癌症甲基组，并使它们暴露在局部甲基化异常中，从而导致肿瘤中出现转录变化。了解癌症中潜在的DNA甲基化及其临床相关性的分子机制仍然至关重要。在这里，作者研究了来自METABRIC队列的1538例乳腺肿瘤和244例正常乳腺组织的RRBS图谱，并报告了表观基因组不稳定性和顺式调控效应。
DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors. Understanding the molecular mechanisms underlying DNA methylation in cancer and its clinical relevance remains crucial. Here, the authors study RRBS-based profiles of 1538 breast tumours and 244 normal breast tissues from the METABRIC cohort and report epigenomic instability and cis-regulatory effects.
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影响因子：
4.8
作者：
Mroz, Edmund A.;Rocco, James W.
通讯作者：
Rocco, James W.
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
64.8
作者：
Pope, Benjamin D.;Ryba, Tyrone;Dileep, Vishnu;Yue, Feng;Wu, Weisheng;Denas, Olgert;Vera, Daniel L.;Wang, Yanli;Hansen, R. Scott;Canfield, Theresa K.;Thurman, Robert E.;Cheng, Yong;Guelsoy, Guenhan;Dennis, Jonathan H.;Snyder, Michael P.;Stamatoyannopoulos, John A.;Taylor, James;Hardison, Ross C.;Kahveci, Tamer;Ren, Bing;Gilbert, David M.
通讯作者：
Gilbert, David M.
影响因子：
22.7
作者：
Ali, H. Raza;Jackson, Hartland W.;Bodenmiller, Bernd
通讯作者：
Bodenmiller, Bernd
影响因子：
30.8
作者：
Landan, Gilad;Cohen, Netta Mendelson;Tanay, Amos
通讯作者：
Tanay, Amos