PO.BCS01.01 · 生物信息与计算
基因共扩增与结构模式揭示癌症中染色体外DNA的原理
Gene co-amplification and structural patterns reveal principles of extrachromosomal DNA in cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌基因在染色体外DNA（ecDNA）上的扩增使肿瘤具有侵袭性且快速演化。ecDNA对孟德尔分离定律的违背使其能够实现摆脱染色体调控约束的极端拷贝数扩增。我们的AmpliconSuite工具集是应用最广泛的全基因组测序数据ecDNA分析工具，目前已应用于超过43,000份肿瘤样本。在此，我们展示了通过这些方法进行大规模整合分析所获得的关于ecDNA生物学的新见解。
我们分析了来自ICGC与Hartwig Medical Foundation合并数据集的6,366例全基因组测序肿瘤，鉴定出2,366个不同的ecDNA，涵盖超过11,000个不同基因。我们系统性的基因共扩增分析揭示了ecDNA上基因选择的显著模式。CDK4-MDM2共扩增主要通过ecDNA发生（占共扩增的75%）。这些位点在12号染色体上通常相距超过11Mbp，但ecDNA结构分析显示，它们在93%的情况下优先组装到同一个ecDNA分子上。这提示存在将细胞周期与p53通路调控因子维持在同一可遗传单元上的选择压力。我们对高频共扩增的分析还揭示，ecDNA优先将染色质重塑因子（NSD3、RSF1）与驱动性癌基因一同包装，同时纳入支持转录和翻译的基因（INTS4、BRF2），从而形成自足式的癌基因“支持”枢纽。结构分析揭示了ecDNA结构的癌种特异性模式，EGFR ecDNA在胶质母细胞瘤中呈现简单结构，而在肺癌和乳腺癌中呈现复杂重排，提示不同癌症中存在不同的形成历史。
我们通过AmpliconRepository.org开放访问这些跨主要癌症队列的ecDNA预测及共扩增分析，目前收录了16,000余份已分析样本和5,000余个已表征的ecDNA扩增。该资源独特地向社区贡献开放，使研究人员能够跨数据集探索模式并验证发现。这些发现揭示了支配ecDNA形成与选择的基本原理，对理解肿瘤异质性、治疗耐药性以及ecDNA靶向治疗所依赖的依赖性具有重要意义。
查看英文原文 English abstract
The amplification of oncogenes on extrachromosomal DNA (ecDNA) enables aggressive, rapidly evolving tumors. Its defiance of Mendelian segregation enables extreme copy number amplifications that escape chromosomal regulatory constraints. Our AmpliconSuite toolset is the most widely used tool for ecDNA analysis in whole genome sequencing data, now deployed on over 43,000 tumor samples. Here, we present novel insights into ecDNA biology enabled through large-scale integrative analysis with these methods.
We analyzed 6,366 whole-genome sequenced tumors from combined ICGC and Hartwig Medical Foundation datasets, identifying 2,366 distinct ecDNA capturing >11,000 different genes. Our systematic gene co-amplification analysis revealed striking patterns of gene selection on ecDNA. CDK4-MDM2 co-amplification occurred predominantly via ecDNA (75% of co-amplifications). These loci, normally separated by >11Mbp on chromosome 12, preferentially assembled onto the same ecDNA molecule 93% of the time as revealed by structural analysis of the ecDNA. This suggests selective pressure for maintaining cell cycle and p53 pathway regulators on the same inheritable unit. Our analysis of frequent co-amplifications also revealed that ecDNA preferentially packages chromatin remodelers (NSD3, RSF1) alongside driver oncogenes, as well as including genes that support transcription and translation (INTS4, BRF2), creating self-contained oncogene “support” hubs. Structural analysis revealed cancer type-specific patterns to ecDNA structures, with EGFR ecDNA showing simple architectures in glioblastoma versus complex rearrangements in lung and breast cancers, suggesting distinct formation histories in different cancers.
Through AmpliconRepository.org, we provide public access to these ecDNA predictions and co-amplification analysis across major cancer cohorts, currently hosting 16,000+ analyzed samples and 5,000+ characterized ecDNA amplifications. Uniquely open to community contributions, this resource enables researchers to explore patterns across datasets and validate findings. These findings reveal fundamental principles governing ecDNA formation and selection, with implications for understanding tumor heterogeneity, therapeutic resistance, and dependencies which underlie ecDNA-targeted therapies.
利益披露 Disclosure
J. Luebeck, None..
E. Huang, None..
F. Kim, None..
B. Dameracharla, None..
M. A. Chan, None..
D. Khatri, None..
K. Fetter, None..
K. Zhu, None..
T. Tabor, None..
S. Kim, None..
H. Kim, None.
P. S. Mischel,
Boundless Bio Inc. g., Board of Directors, non-salaried role), Stock, Scientific Advisory Board chair.
J. P. Mesirov, None.
V. Bafna,
Boundless Bio Inc. Stock, Other, Scientific advisory board.
Abterra Stock, Scientific advisory board.