Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer

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. Epigenetic biallelic inactivation in prostate cancer remains to be explored. Here, the authors develop a computational method Epi2Hit that integrates the hemizygous genomic disruptions with patterns of hypermethylation at regulatory CpG sites to identify biallelic inactivation in tumour suppressor genes.

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Nature Communications
Published
2026-09-09
DOI
https://doi.org/10.1038/s41467-026-72182-5
Primary Topic
Epigenetics and DNA Methylation
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article
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article

Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer

Esther Baena, Jakob S. Jespersen, Pavlo Lutsik, Ruining Dong et al.
Nature Communications
Epigenetics and DNA Methylation
article

Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer

Esther Baena, Jakob S. Jespersen, Pavlo Lutsik, Ruining Dong, Lars Feuerbach, David C. Wedge, Bethany K. Campbell, F. G. Rodriguez Gonzalez, Francesco Favero, G. Steven Bova, Clarissa Gerhäuser, Diogo Pellegrina, Rosalind A. Eeles, Ángel Fernández-Sanromán, Géraldine Cancel‐Tassin, Fabian Falkenbach, Lúcio Queiroz, Bárbara Hernando, Daria Kiriy, G. Maria Jakobsdottir, Philippe Lamy, Robert G. Bristow, Ken Chow, Marek Cmero, Angelo Corso Faini, Vincent J. Gnanapragasam, Andreas Gruber, Takafumi N. Yamaguchi, Vanessa M. Hayes, Kevin Cheng, Abraham Gihawi, Breon Feran, Tobias Rausch, Daniel Barrowdale, Etsehiwot G. Girma, Emre Esentürk, Alain Bergeron, Atef Sahli, M.J. Clarkson, Geoff Macintyre, Adam Butler, Housheng Hansen He, Zsofia Kote‐Jarai, Mark N. Brook, Kira Furlano, Anthony T. Papenfuss, Bernard J. Pope, Chol-Hee Jung, Benedikt Brors, Brian D. Robinson, Francesca Khani, Yunfan Fu, Justin Bedő, Yaobo Xu, Massimo Loda, Ryan Carelli, Anis Hamid, Yves Fradet, Ramyar Molania, Jessica Heilmann, Luigi Marchionni, Christopher M. Hovens, Karina D. Sørensen, Peter Georgeson, Claudio Zanettini, Alejandro Berlín, Daniel S. Brewer, Sebastian Uhrig, Alessio Locallo, Gregory Leeman, Marina Torres, Niall M. Corcoran, Tony Costello, Wikum Dinalankara, Andrew Erickson, Lucy Barton, Juan Maria Roldan-Romero, Giuseppe N. Fanelli, Philip Dundee, Olivier Cussenot, Housheng Hansen He, Eddie L. Imada, Nening Dennis, Noora Al-Muftah, Harveer Dev, Wi Burns, Zsofia Kote-Jarai, Massimo Loda, Colin Collins, Anis Hamid, Pan Prostate Cancer Group (PPCG), Andre V. Olsen, Michael Borre, Chris Foster, Melissa Cheung, Anthony T. Papenfuss
article en

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. Epigenetic biallelic inactivation in prostate cancer remains to be explored. Here, the authors develop a computational method Epi2Hit that integrates the hemizygous genomic disruptions with patterns of hypermethylation at regulatory CpG sites to identify biallelic inactivation in tumour suppressor genes.

Nature CommunicationsVol. 17(1)
Broad Institute (US), University of East Anglia (GB), Ontario Institute for Cancer Research (CA), University of Copenhagen (DK), The University of Sydney (AU), European Bioinformatics Institute (GB), The Royal Melbourne Hospital (AU), Royal Marsden NHS Foundation Trust (GB), University Health Network (CA), Memorial Sloan Kettering Cancer Center (US), NewYork–Presbyterian Hospital (US), Institute of Cancer Research (GB), Université du Québec à Montréal (CA), University of California, Los Angeles (US), The University of Melbourne (AU), German Cancer Research Center (DE), University of Toronto (CA), University of Konstanz (DE), Walter and Eliza Hall Institute of Medical Research (AU), Aarhus University (DK), Cornell University (US), Heidelberg University (DE), University of Cambridge (GB), Norwich Research Park (GB), New York Hospital Queens (US), Cancer Research UK (GB), Nuffield Orthopaedic Centre (GB), University Hospital Heidelberg (DE), Aarhus University Hospital (DK), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Copenhagen University Hospital (DK), Princess Margaret Cancer Centre (CA), Rigshospitalet (DK), University of Manchester (GB), Melbourne Bioinformatics (AU), University of Oxford (GB), Cancer Research UK Cambridge Center (GB), Spanish National Cancer Research Centre (ES), Presbyterian Hospital (US), Royal Brompton Hospital (GB), Victorian Comprehensive Cancer Centre (AU), Tampere University Hospital (FI), Cancer Research UK Manchester Institute (GB), Centre d'Enseignement et de Recherche en Environnement Atmosphérique (FR), Tampere University (FI), The Christie NHS Foundation Trust (GB), New York Genome Center (US), European Molecular Biology Laboratory (DE), Addenbrooke's Hospital (GB), Université Laval (CA), Weill Cornell Medicine (US), University of Pretoria (ZA), Charité - Universitätsmedizin Berlin (DE), Heidelberg University (US), Epigenomics (Germany) (DE), KU Leuven (BE)
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