美国麻省总医院Bradley E. Bernstein、George D. Demetri和Yotam Drier等研究人员发现，染色体拓扑结构的改变驱动琥珀酸脱氢酶（SDH）缺陷型胃肠道间质瘤（GIST）的致癌发生。 2019年10月16日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，表观遗传改变在癌症中很普遍，但是其潜在机制和因果关系仍然知之甚少。一种GIST亚型缺乏典型的激酶突变，但具有SDH缺陷和整体DNA过度甲基化。

研究人员将这种高甲基化与激活致癌程序的基因组拓扑变化联系起来。为了系统地调查表观遗传变化，研究人员在KIT突变型、PDGFRA突变型和SDH缺陷型GIST中绘制了DNA甲基化、CTCF绝缘子、增强子和染色体拓扑结构图谱。尽管这些亚型具有相似的增强子状态，但研究人员鉴定了数百种假定的绝缘子，其中DNA甲基化取代了SDH缺陷型GIST中的CTCF结合。研究人员关注的是一种被破坏的绝缘子，该绝缘子通常会从FGF4癌基因中分离出一个核心GIST超级增强子。该绝缘子的反复丢失会改变SDH缺陷型GIST中的基因座拓扑结构，从而使增强子和癌基因之间发生异常的物理相互作用。

CRISPR介导的SDH完整型GIST模型中相应CTCF基序的敲除破坏了边界并强烈上调了FGF4表达。研究人员还发现了KIT癌基因附近的第二次复发性绝缘子丢失事件，该事件在SDH缺陷型GIST中也得到了高度表达。

最后，研究人员从SDH缺陷型GIST建立了患者来源的异种移植物（PDX）模型，该移植物忠实地维持了亲本肿瘤的表观遗传学，包括超甲基化和绝缘子缺陷。这一PDX模型对FGF受体（FGFR）抑制剂高度敏感，对FGFR和KIT联合抑制更敏感，从而验证了潜在表观遗传损伤的功能重要性。这项研究揭示了表观遗传学改变如何在缺失经典激酶突变的情况下驱动致癌程序，从而对癌症异常途径的机制靶向具有影响。

附：英文原文

Title: Altered chromosomal topology drives oncogenic programs in SDH-deficient GIST

Author: William A Flavahan, Yotam Drier, Sarah E. Johnstone, Matthew L. Hemming, Daniel R. Tarjan, Esmat Hegazi, Sarah J. Shareef, Nauman M. Javed, Chandrajit P. Raut, Benjamin K. Eschle, Prafulla C. Gokhale, Jason L. Hornick, Ewa T. Sicinska, George D. Demetri, Bradley E. Bernstein

Issue&Volume: 2019-10-16

Abstract: 

Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood1–3. A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation4,5. Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.

DOI: 10.1038/s41586-019-1668-3

Source:https://www.nature.com/articles/s41586-019-1668-3