Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Research output: Contribution to journalJournal articleResearchpeer-review

Verena Zuber, Francesco Bettella, Aree Witoelar, Ole A. Andreassen, Ian G. Mills, Alfonso Urbanucci, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A. Haiman, Johanna Schleutker, Maren Weischer, Ruth C. Travis, David Neal & 31 others Paul Pharoah, Kay Tee Khaw, Janet L. Stanford, William J. Blot, Stephen Thibodeau, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R. Teixeira, Hardev Pandha, Georgia Chenevix-Trench, Manjeet Humphreys, R. J. Hung, Y. Han, P. Brennan, H. Bickeböller, A. Rosenberger, R. S. Houlston, N. Caporaso, M. T. Landi, X. Wu, Qin Wang, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, the PRACTICAL Consortium, the COGS-CRUK GWAS, the BCAC Consortium, the TRICL Consortium

Background: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Results: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. Conclusions: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.

Original languageEnglish
Article number270
JournalBMC Genomics
Volume18
Number of pages11
ISSN1471-2164
DOIs
Publication statusPublished - 31 Mar 2017

    Research areas

  • BRD4, Breast cancer risk, Chromatin, Functional annotation, Genome-wide association studies, Prostate cancer risk, Risk loci, Schizophrenia, SNPs, Super-enhancer

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