Epigenomic charting and functional annotation of risk loci in renal cell carcinoma

Amin H. Nassar, Sarah Abou Alaiwi, Sylvan C. Baca, Elio Adib, Rosario I. Corona, Ji-Heui Seo, Marcos A. S. Fonseca, Sandor Spisak, Talal El Zarif, Viktoria Tisza, David A. Braun, Heng Du, Monica He, Abdallah Flaifel, Michel Alchoueiry, Thomas Denize, Sayed G. Matar, Andres Acosta, Sachet Shukla, Yue Hou, John Steinharter, Gabrielle Bouchard, Jacob E. Berchuck, Edward O’Connor, Connor Bell, Pier Vitale Nuzzo, Gwo-Shu Mary Lee, Sabina Signoretti, Michelle S. Hirsch, Mark Pomerantz, Elizabeth Henske, Alexander Gusev, Kate Lawrenson, Toni K. Choueiri (), David J. Kwiatkowski () and Matthew L. Freedman ()
Additional contact information
Amin H. Nassar: Yale New Haven Hospital
Sarah Abou Alaiwi: Brigham and Women’s Hospital
Sylvan C. Baca: Brigham and Women’s Hospital
Elio Adib: Brigham and Women’s Hospital
Rosario I. Corona: Cedars-Sinai Medical Center
Ji-Heui Seo: Dana-Farber Cancer Institute
Marcos A. S. Fonseca: Cedars-Sinai Medical Center
Sandor Spisak: Dana-Farber Cancer Institute
Talal El Zarif: Brigham and Women’s Hospital
Viktoria Tisza: Dana-Farber Cancer Institute
David A. Braun: Yale New Haven Hospital
Heng Du: Brigham and Women’s Hospital
Monica He: Dana-Farber Cancer Institute
Abdallah Flaifel: Brigham and Women’s Hospital
Michel Alchoueiry: Brigham and Women’s Hospital
Thomas Denize: Brigham and Women’s Hospital
Sayed G. Matar: Brigham and Women’s Hospital
Andres Acosta: Brigham and Women’s Hospital
Sachet Shukla: Dana-Farber Cancer Institute
Yue Hou: Dana-Farber Cancer Institute
John Steinharter: Dana-Farber Cancer Institute
Gabrielle Bouchard: Dana-Farber Cancer Institute
Jacob E. Berchuck: Brigham and Women’s Hospital
Edward O’Connor: Dana-Farber Cancer Institute
Connor Bell: Dana-Farber Cancer Institute
Pier Vitale Nuzzo: Dana-Farber Cancer Institute
Gwo-Shu Mary Lee: Dana-Farber Cancer Institute
Sabina Signoretti: Brigham and Women’s Hospital
Michelle S. Hirsch: Brigham and Women’s Hospital
Mark Pomerantz: Dana-Farber Cancer Institute
Elizabeth Henske: Brigham and Women’s Hospital
Alexander Gusev: Dana-Farber Cancer Institute
Kate Lawrenson: Cedars-Sinai Medical Center
Toni K. Choueiri: Brigham and Women’s Hospital
David J. Kwiatkowski: Brigham and Women’s Hospital
Matthew L. Freedman: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.

Date: 2023
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DOI: 10.1038/s41467-023-35833-5

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