Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability
Year: 2026
Type: article
Abstract: By generating 194 epigenomic and transcriptomic datasets from 57 human tissue samples using H3K27ac and HIF2α chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA sequencing, we provide a comprehensive, integrated characterization of clear cell renal cell carcinoma (ccRCC) across normal, tumor, and metastatic states. Our analyses provide several insights into ccRCC biology. First, we demonstrate significant reprogramming of enhancer and HIF2α cistromes as well as chromatin accessibility during the normal-to-tumor transition, whereas localized and metastatic tumors show minimal epigenomic differences. Second, we show reactivation of kidney-specific developmental pathways driving malignancy. Third, we perform a cistrome-wide association study in ccRCC, validating five established RCC risk loci and identifying six novel loci, including a locus at 12q24 linked to SCARB1 that was functionally validated. These datasets provide new perspectives on the role of developmental pathways in ccRCC tumorigenesis, insights into epigenetic mechanisms of ccRCC heritability, and a comprehensive epigenomic atlas for the research community.
Source: Cell Reports
Authors: Sarah Abou Alaiwi, Elio Adib, Ziwei Zhang, Sandor Spisak, Aurel Prosz, Paulo Cordeiro, Talal El Zarif, Zsófia Márta Sztupinszki, Amin H. Nassar, Ji-Heui Seo, Rianna Campbell, John A. Steinharter, Mitchell Machiela, Diptavo Dutta, Stephen Chanock, Mark Purdue, Mark Pomerantz, Sabina Signoretti, Zoltan Szallasi, Alexander Gusev, Sylvan C. Baca, Toni K. Choueiri, Matthew L. Freedman
Institutions: Yale New Haven Hospital, Yale University, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Dana-Farber Brigham Cancer Center, Harvard University, Dana-Farber/Harvard Cancer Center, Institute of Molecular Life Sciences, Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Broad Institute, Boston Children's Hospital, University of Vermont, National Institutes of Health, Division of Cancer Epidemiology and Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Damon Runyon Cancer Research Foundation, Dana Foundation, Pan-Massachusetts Challenge, Harvard Medical School, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Fund for Innovation in Cancer Informatics, National Institutes of Health, National Cancer Institute
Awards: HARNESSING EPIGENOMICS TO DETECT AND TARGET SARCOMATOID DIFFERENTIATION IN RENAL CELL CARCINOMA., DF/HCC Kidney Cancer SPORE, Elucidating prostate cancer risk mechanisms through large-scale cistrome wide association studies, Elucidation of the genetic mechanisms driving prostate tumorigenesis through integrative computational and functional approaches, DF/HCC Prostate SPORE
OpenAlex ID: W7128709072