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https://bura.brunel.ac.uk/handle/2438/34121| Title: | Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer |
| Authors: | Kiriy, Daria Favero, Francesco Gerhäuser, Clarissa Heilmann, Jessica Lutsik, Pavlo Gonzalez, Francisco German Rodriguez Locallo, Alessio Jespersen, Jakob Schmidt Gruber, Andreas J Olsen, Andre V Hernando, Barbara Fu, Yunfan Haberland, Valleriia Furlano, Kira Georgeson, Peter Graefen, Markus Phal, Pramit M Hong, Matthew KH Hutchison, William J Jaratlerdsiri, Weerachai Jiang, Jue Schlomm, Thorsten Cheng, Kevin CL Mensah, Nana Ureta, Jennifer Keane, Thomas Kerger, Michael Kerry, Giselle Kurganovs, Natalie Pirhady, Parsa Lach, Radoslaw Lamb, Alastair D Pellegrina, Diogo Lim, Beng Lu, Yong-Jie Lynch, Andy G Van Loo, Peter Mills, Ian Milne-Clark, Toby Nguyen, Anne Norden, Sam Imada, Eddie L Bova, G Steven Reimand, Jüri Nuzzo, Pier Vitale Nykter, Matti Macintyre, Geoff Olofinsae, Samson Voith von Voithenberg, Lena Omar, Mohamed Pakula, Hubert Pan, Yidan Park, Daniel J Pederzoli, Filippo Weischenfeldt, Joachim Plass, Christoph Raine, Keiran Rodrigues, Silvia Pereira, Ronnie Rodrigues Xu, Yaobo Khani, Francesca Rubin, Alan F Ryan, Andrew Jung, Chol-Hee Sankar, Aravind Pan Prostate Cancer Group (PPCG) Schlotmann, Balthasar C Stuchbery, Ryan Sültmann, Holger Brewer, Daniel S Taylor, Avigail Wakefield, Matthew Warren, Anne Wirth, Christopher Woodcock, Dan J Baena, Esther Zanettini, Claudio Zhang, Jingjing Bristow, Robert G Yamaguchi, Takafumi N Ziuboniewicz, Aleksandra S Simon, Ronald Sauter, Guido Batra, Rajbir RN Kote-Jarai, Zsofia Cooper, Colin S Brook, Mark N Brors, Benedikt Butler, Adam Cancel-Tassin, Géraldine Costello, Tony Corcoran, Niall M Lamy, Philippe P Barrowdale, Daniel Cussenot, Olivier Eeles, Ros A Gihawi, Abraham Girma, Etsehiwot G Torres, Marina Gnanapragasam, Vincent J Hamid, Anis Jakobsdottir, G Maria Hayes, Vanessa M He, Housheng Hansen Hovens, Christopher M Bedő, Justin Leeman, Gregory Loda, Massimo Marchionni, Luigi Molania, Ramyar Grima, Corinna Fernández-Sanromán, Angel Dennis, Nening Papenfuss, Anthony T Pope, Bernard Queiroz, Lucio R Rausch, Tobias Bergeron, Alain Robinson, Brian Sahli, Atef Sørensen, Karina D Uhrig, Sebastian Wedge, David C Dev, Harveer Roldan-Romero, Juan Maria Barton, Lucy Corcoran, Niall M Gnanapragasam, Vincent J Mangiola, Stefano He, Xiaotong Hamid, Anis He, Housheng Hansen Hall, Grace A Hovens, Christopher M Dinalankara, Wikum Kote-Jarai, Zsofia Loda, Massimo Molania, Ramyar Papenfuss, Anthony T Al-Muftah, Noora Berlin, Alejandro Borre, Michael Burns, Wi Campbell, Bethany K Penington, Jocelyn McCoy, Patrick Carelli, Ryan Cheung, Melissa Massie, Charlie E Chow, Ken Clarkson, Michael J Cmero, Marek Collins, Colin Holmes, Vivien Faini, Angelo Corso Dong, Ruining Dundee, Philip Foster, Chris Erickson, Andrew Tennstedt, Pierre Esentürk, Emre Hong, Chen Peters, Justin S Falkenbach, Fabian Fanelli, Giuseppe N Feran, Breon Feuerbach, Lars Mehmood, Arfa Fradet, Yves |
| Issue Date: | 9-Sep-2026 |
| Publisher: | Springer Nature |
| Citation: | Kiriy, D. et al. for the Pan Prostate Cancer Group (PPCG) (2026) 'Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer', Nature Communications, 17(1), 9646, pp. 1–20. doi: 10.1038/s41467-026-72182-5. |
| Abstract: | The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes involving DNA methylation of promoter and enhancer regions of one allele and genomic loss of the other allele. We apply Epi2Hit to a cohort of 2,021 prostate cancers to discover tumour suppressor genes. In particular, we identify epigenetic biallelic inactivation of ZFHX3 at a recurrence level similar to TP53. Biallelic inactivation of ZFHX3, a transcriptional repressor, leads to upregulation of oncogenes, including MYC and a shorter time to metastasis. Finally, we provide evidence that epigenetic silencing as 2nd hit is particularly enriched in regions with nearby essential genes, precluding homozygous loss. |
| Description: | Data availability:
PPCG dataset comprises whole-genome sequencing (WGS), RNA-seq, DNA methylation, clinical, and histopathological data from 2,021 prostate cancer donors. Due to the sensitive nature of human genomic/clinical data and participant-consent restrictions, PPCG data are provided under controlled access and are available only for approved research purposes. Raw genome sequencing data have been deposited in the European Genome-Phenome 1360 Archive (EGA) under the study ID EGAS00001002876 and is described in the Reporting Summary and our companion manuscript29. In addition, PPCG working project data (e.g., variant calls, pipeline outputs and intermediate analyses) and harmonised RNA-seq/methylation data are made available to approved projects through secure transfer (Globus), and clinical/histopathological data are hosted in a GDPR-compliant secure environment (REDCap); access is limited to approved PPCG researchers. Access to PPCG controlled data requires submission of a Project Concept Form, available at https://panprostate.org, and approval by the PPCG Steering Committee. Requests are submitted by emailing the completed form to PPCG@icr.ac.uk. We will respond to the data access request within 14 days. We will provide guidance on the application process; access, once granted, is provided for the duration of the approved project under the applicable data access agreement/terms. To support reproducibility without redistribution of controlled PPCG data, we provide a compact, self-contained example dataset in the project repository that is sufficient to run the Epi2Hit workflow end-to-end and reproduce representative outputs. Specifically, the repository includes a TCGA-PRAD chromosome 8 example dataset (450 K methylation β-values for chr8, a matched gene expression matrix, prostate ATAC-seq peaks, ChromHMM segmentation, and Hi-C loops), together with example mutation calls and copy-number segment inputs used for downstream biallelic analyses. These files are provided under the repository’s data/ directory and are used by analysis/TCGA_run.ipynb (and the containerised demo) to reproduce the main workflow outputs on the example dataset. The publicly available data used in this study are available in the NCBI Gene Expression Omnibus (GEO) database under accession code GSE164347 (prostate Hi-C loops): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE16434737. The publicly available data used in this study are available in the GEO database under accession code GSE188797 (tumour ATAC-seq peaks): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE18879736. The publicly available data used in this study are available in the GEO database under accession code GSE49402 (GSM1208743, ZFHX3 ChIP-seq): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4940272. The publicly available data used in this study are available from the ENCODE Project database (epigenetic marks (H3K4me3, H3K27ac) and CTCF tracks derived for prostate cancer cells (PC-3, C4-2B)): https://www.encodeproject.org/110. The remaining data are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper. Code availability: Code used to generate results and plots are available at https://github.com/panprostate/Epi2Hit. A static version of the code is available at https://doi.org/10.5281/ZENODO.18788787 [122. Kiriy, D. Recurrent Mechanisms of Biallelic Epigenetic Inactivation Reveal New Putative Tumour Suppressor Genes in Prostate Cancer. (Zenodo, 2026). https://doi.org/10.5281/ZENODO.18788787.]. |
| URI: | https://bura.brunel.ac.uk/handle/2438/34121 |
| DOI: | https://doi.org/10.1038/s41467-026-72182-5 |
| Appears in Collections: | Department of Computer Science Research Papers |
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