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DOI 10.1038/s41467-026-72182-5

Медицинская библиотека · Nature communications · 2026

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

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, Cheng Kevin Cl, Pellegrina Diogo, Macintyre Geoff, Bova G Steven, Brewer Daniel S, Bristow Robert G, Brook Mark N, Brors Benedikt, Butler Adam, Cancel-Tassin Géraldine, Corcoran Niall M, Cussenot Olivier, Eeles Ros A, Gihawi Abraham, Girma Etsehiwot G, Gnanapragasam Vincent J, Hamid Anis, Hayes Vanessa M, He Housheng Hansen, Hovens Christopher M, Imada Eddie L, Jakobsdottir G Maria, Jung Chol-Hee, Khani Francesca, Kote-Jarai Zsofia, Lamy Philippe P, Leeman Gregory, Loda Massimo, Marchionni Luigi, Molania Ramyar, Papenfuss Anthony T, Pope Bernard, Queiroz Lucio R, Rausch Tobias, Robinson Brian, Sahli Atef, Sørensen Karina D, Uhrig Sebastian, Wedge David C, Xu Yaobo, Yamaguchi Takafumi N, Zanettini Claudio, Pan Prostate Cancer Group (PPCG), Cooper Colin S, Schlomm Thorsten, Reimand Jüri, Weischenfeldt Joachim

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Аннотация

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.

Для цитирования: 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, Cheng Kevin Cl, Pellegrina Diogo, Macintyre Geoff, Bova G Steven, Brewer Daniel S, Bristow Robert G, Brook Mark N, Brors Benedikt, Butler Adam, Cancel-Tassin Géraldine, Corcoran Niall M, Cussenot Olivier, Eeles Ros A, Gihawi Abraham, Girma Etsehiwot G, Gnanapragasam Vincent J, Hamid Anis, Hayes Vanessa M, He Housheng Hansen, Hovens Christopher M, Imada Eddie L, Jakobsdottir G Maria, Jung Chol-Hee, Khani Francesca, Kote-Jarai Zsofia, Lamy Philippe P, Leeman Gregory, Loda Massimo, Marchionni Luigi, Molania Ramyar, Papenfuss Anthony T, Pope Bernard, Queiroz Lucio R, Rausch Tobias, Robinson Brian, Sahli Atef, Sørensen Karina D, Uhrig Sebastian, Wedge David C, Xu Yaobo, Yamaguchi Takafumi N, Zanettini Claudio, Pan Prostate Cancer Group (PPCG), Cooper Colin S, Schlomm Thorsten, Reimand Jüri, Weischenfeldt Joachim. Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer.. Nature communications. 2026. DOI: 10.1038/s41467-026-72182-5.

Предметные рубрики MeSH

Prostatic NeoplasmsDNA MethylationHumansGenes, Tumor SuppressorEpigenesis, GeneticGene Expression Regulation, NeoplasticMaleGene SilencingPromoter Regions, GeneticAllelesHomeodomain ProteinsWhole Genome Sequencing
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