Title | Three-dimensional genome landscape of primary human cancers. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Yost KE, Zhao Y, Hung KL, Zhu K, Xu D, M Corces R, Shams S, Louie BH, Sarmashghi S, Sundaram L, Luebeck J, Clarke S, Doane AS, Granja JM, Choudhry H, Imielinski M, Cherniack AD, Khurana E, Bafna V, Felau I, Zenklusen JC, Laird PW, Curtis C, Greenleaf WJ, Chang HY |
Corporate Authors | Cancer Genome Atlas Analysis Network |
Journal | Nat Genet |
Volume | 57 |
Issue | 5 |
Pagination | 1189-1200 |
Date Published | 2025 May |
ISSN | 1546-1718 |
Keywords | Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Neoplasms, Oncogenes, Tumor Microenvironment, Whole Genome Sequencing |
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 |
Alternate Journal | Nat Genet |
PubMed ID | 40355593 |
PubMed Central ID | PMC12081301 |
Grant List | DP1HG013599 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 1U24CA264023-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / F99 CA274692 / CA / NCI NIH HHS / United States F99 CA253729 / CA / NCI NIH HHS / United States U24 CA264029 / CA / NCI NIH HHS / United States CGCATF-2021/100025 / / Cancer Research UK (CRUK) / R01GM114362 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01 CA218668 / CA / NCI NIH HHS / United States R35-CA209919 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / U24CA264379 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / 1U24CA264029-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / R01NS128028 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / U24 CA264009 / CA / NCI NIH HHS / United States R01CA218668 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / RM1 HG007735 / HG / NHGRI NIH HHS / United States NIH F99CA274692 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / DP1 HG013599 / HG / NHGRI NIH HHS / United States R01 HL171611 / HL / NHLBI NIH HHS / United States U24 CA264379 / CA / NCI NIH HHS / United States U24 CA264032 / CA / NCI NIH HHS / United States DGE-1656518 / / National Science Foundation (NSF) / U24 CA264021 / CA / NCI NIH HHS / United States RM1-HG007735 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) / OT2 CA278635 / CA / NCI NIH HHS / United States R01 NS128028 / NS / NINDS NIH HHS / United States U24CA264032 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / OT2CA278635 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / CGCSDF-2021\100007 / / Cancer Research UK (CRUK) / U24 CA264023 / CA / NCI NIH HHS / United States R01 GM114362 / GM / NIGMS NIH HHS / United States R35 CA209919 / CA / NCI NIH HHS / United States NIH F99CA253729 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) / R01HL171611 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / |