近日，美国斯坦福大学医学院教授Howard Y. Chang及其团队的最新研究提出了原发性人类癌症的三维基因组图谱。该研究于2025年5月12日发表于国际一流学术期刊《自然—遗传学》杂志上。

在这里，课题组研究人员分析了来自癌症基因组图谱的69个肿瘤样本的三维基因组结构和增强子连接组，涵盖15种原发性人类癌症类型。该课题组发现了人类癌症中超过100种致癌基因的增强子图像的以下三种原型：静态、选择性增益或动态重新布线。综合分析揭示了肿瘤微环境中与免疫逃逸相关基因的非癌细胞增强子景观。深度全基因组测序和增强子连接组图谱提供了癌症基因组中不同结构变异的准确检测和验证，并揭示了非编码点突变、基因组倒置、易位和焦点扩增等不同的增强子重接线后果。染色体外DNA在几种类型的病灶扩增机制中促进了更广泛的增强子重新布线。这些结果提示了一种系统的方法来理解癌症病因学和治疗中的基因组拓扑。

据悉，基因组构象是远端增强子转录调控的基础，癌症中的基因组重排可以改变关键的调控相互作用。

附：英文原文

Title: Three-dimensional genome landscape of primary human cancers

Author: Yost, Kathryn E., Zhao, Yanding, Hung, King L., Zhu, Kaiyuan, Xu, Duo, Corces, M. Ryan, Shams, Shadi, Louie, Bryan H., Sarmashghi, Shahab, Sundaram, Laksshman, Luebeck, Jens, Clarke, Stanley, Doane, Ashley S., Granja, Jeffrey M., Choudhry, Hani, Imieliski, Marcin, Cherniack, Andrew D., Khurana, Ekta, Bafna, Vineet, Felau, Ina, Zenklusen, Jean C., Laird, Peter W., Curtis, Christina, Greenleaf, William J., Chang, Howard Y.

Issue&Volume: 2025-05-12

Abstract: Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy.

DOI: 10.1038/s41588-025-02188-0

Source: https://www.nature.com/articles/s41588-025-02188-0