Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
| العنوان: | Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential |
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| المؤلفون: | Jeroen Kneppers, Tesa M. Severson, Joseph C. Siefert, Pieter Schol, Stacey E. P. Joosten, Ivan Pak Lok Yu, Chia-Chi Flora Huang, Tunç Morova, Umut Berkay Altıntaş, Claudia Giambartolomei, Ji-Heui Seo, Sylvan C. Baca, Isa Carneiro, Eldon Emberly, Bogdan Pasaniuc, Carmen Jerónimo, Rui Henrique, Matthew L. Freedman, Lodewyk F. A. Wessels, Nathan A. Lack, Andries M. Bergman, Wilbert Zwart |
| المساهمون: | Chemical Biology, Immunoengineering, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Altıntaş, Umut Berkay, Kneppers, J., Severson, T.M., Siefert, J.C., Schol, P., Joosten, S.E.P., Yu, I.P.L., Huang, C.F., Morova, T., Giambartolomei, C., Seo, J.H., Baca, S.C., Carneiro, I., Emberly, E., Pasaniuc, B., Jerónimo, C., Henrique, R., Freedman, M.L., Wessels, L.F.A., Bergman, A.M., Zwart, W., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Graduate School of Sciences and Engineering, Department of Computational Sciences and Engineering |
| المصدر: | Nature Communications, 13(1):7367. Nature Publishing Group Nature Communications |
| بيانات النشر: | Nature Publishing Group, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Male, Multidisciplinary, Nucleic Acid, Prostatic Neoplasms/genetics, Androgen/genetics, Prostate, General Physics and Astronomy, Prostatic Neoplasms, General Chemistry, Regulatory Sequences, Nucleic Acid, SDG 3 – Goede gezondheid en welzijn, Receptors, Androgen/genetics, General Biochemistry, Genetics and Molecular Biology, Chromatin, Medicine, Biochemistry, SDG 3 - Good Health and Well-being, Receptors, Androgen, Receptors, Humans, Prostatic neoplasms, Receptors, androgen, Regulatory sequences, nucleic acid, Regulatory Sequences |
| الوصف: | Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact. We would like to acknowledge the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support and the NKI Research High-Performance Computing (RHPC) facility for computational infrastructure. We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. This work was supported by the Prostate Cancer Foundation (21CHAL04), Department of Defense (W81XWH-21-1-0234, W81XWH-19-1-0565), Oncode Institute and Alpe d’HuZes/KWF Dutch Cancer Society (10084). |
| وصف الملف: | application/pdf; pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::55de06c697f3dfb6b6c8e581994da01bTest https://research.tue.nl/en/publications/b617b6a0-0f0f-4fdd-8dda-b4f9c2dcfa38Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....55de06c697f3dfb6b6c8e581994da01b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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