Epigenetic profiling demarcates molecular subtypes of muscle-invasive bladder cancer

Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitiv...

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Published inScientific reports Vol. 10; no. 1
Main Authors van der Vos, K. E., Vis, D. J., Nevedomskaya, E., Kim, Y., Choi, W., McConkey, D., Wessels, L. F. A., van Rhijn, B. W. G., Zwart, W., van der Heijden, M. S.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 02.07.2020
Nature Publishing Group
Subjects
631/337/100/2285
631/337/176
692/4028/67/589/1336
Bladder cancer
Cancer
Chemotherapy
Chromatin
DNA methylation
Enhancers
Epigenetics
Genomes
Humanities and Social Sciences
Invasiveness
Methylation
multidisciplinary
Next-generation sequencing
Ribonucleic acid
RNA
Science
Science (multidisciplinary)
Tumors
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Summary:Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-67850-5