DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.
DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.
复制标题
DOI：
10.1038/nm.4273
复制
发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Tomazou EM
中科院分区：
文献类型：
--
作者：
Sheffield NC;Pierron G;Klughammer J;Datlinger P;Schönegger A;Schuster M;Hadler J;Surdez D;Guillemot D;Lapouble E;Freneaux P;Champigneulle J;Bouvier R;Walder D;Ambros IM;Hutter C;Sorz E;Amaral AT;de Álava E;Schallmoser K;Strunk D;Rinner B;Liegl-Atzwanger B;Huppertz B;Leithner A;de Pinieux G;Terrier P;Laurence V;Michon J;Ladenstein R;Holter W;Windhager R;Dirksen U;Ambros PF;Delattre O;Kovar H;Bock C;Tomazou EM
儿童和年轻人的发育性肿瘤几乎没有遗传改变，但它们具有不同的临床表现。以尤文肉瘤为中心，我们试图确定遗传同质性癌症中表观遗传异质性的患病率和特征。我们对一个大的尤文肉瘤肿瘤队列进行了基因组规模的DNA甲基化测序，并在三个水平上分析了表观遗传异质性：癌症之间，肿瘤之间和肿瘤内。我们观察到一致的DNA低甲基化的增强子调节的疾病定义EWS-FLI 1融合蛋白，从而建立表观基因组增强子重编程作为一个普遍存在的和特征性的尤文肉瘤。肿瘤之间的DNA甲基化差异确定了尤文肉瘤潜在的连续疾病谱，这反映了EWS-FLI 1调控特征的强度以及间充质和干细胞特征之间的连续性。肿瘤内存在大量的表观遗传异质性，特别是在转移性疾病患者中。总之，我们的研究提供了尤文肉瘤表观遗传异质性的全面评估，从而强调了在癌症生物学和个性化医疗背景下考虑肿瘤异质性的非遗传方面的重要性。
Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.
登录
查看更多内容
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
82.9
作者：
Li S;Garrett-Bakelman FE;Chung SS;Sanders MA;Hricik T;Rapaport F;Patel J;Dillon R;Vijay P;Brown AL;Perl AE;Cannon J;Bullinger L;Luger S;Becker M;Lewis ID;To LB;Delwel R;Löwenberg B;Döhner H;Döhner K;Guzman ML;Hassane DC;Roboz GJ;Grimwade D;Valk PJ;D'Andrea RJ;Carroll M;Park CY;Neuberg D;Levine R;Melnick AM;Mason CE
通讯作者：
Mason CE
影响因子：
14.9
作者：
Burger L;Gaidatzis D;Schübeler D;Stadler MB
通讯作者：
Stadler MB
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
50.3
作者：
Landau DA;Clement K;Ziller MJ;Boyle P;Fan J;Gu H;Stevenson K;Sougnez C;Wang L;Li S;Kotliar D;Zhang W;Ghandi M;Garraway L;Fernandes SM;Livak KJ;Gabriel S;Gnirke A;Lander ES;Brown JR;Neuberg D;Kharchenko PV;Hacohen N;Getz G;Meissner A;Wu CJ
通讯作者：
Wu CJ