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

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; 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

doi:10.1186/s12864-017-3620-y

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

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 NealPaul 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

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

17 Citationer (Scopus)

44 Downloads (Pure)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	270
Tidsskrift	BMC Genomics
Vol/bind	18
Antal sider	11
ISSN	1471-2164
DOI	https://doi.org/10.1186/s12864-017-3620-y
Status	Udgivet - 31 mar. 2017

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Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancerForlagets udgivne version, 1,24 MBLicens: CC BY

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Zuber, V., Bettella, F., Witoelar, A., Andreassen, O. A., Mills, I. G., Urbanucci, A., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., Schleutker, J., Weischer, M., Travis, R. C., ... the PRACTICAL Consortium, the COGS-CRUK GWAS, the BCAC Consortium, the TRICL Consortium (2017). Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genomics, 18, [270]. https://doi.org/10.1186/s12864-017-3620-y

Zuber, V, Bettella, F, Witoelar, A, Andreassen, OA, Mills, IG, Urbanucci, A, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Weischer, M, Travis, RC, Neal, D, Pharoah, P, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Chenevix-Trench, G, Humphreys, M, Hung, RJ, Han, Y, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Wu, X, Wang, Q, Bojesen, SE, Nielsen, SF, Nordestgaard, BG & the PRACTICAL Consortium, the COGS-CRUK GWAS, the BCAC Consortium, the TRICL Consortium 2017, 'Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer', BMC Genomics, bind 18, 270. https://doi.org/10.1186/s12864-017-3620-y

@article{00cec9f4a609444480a8ec33d2d98e63,

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

abstract = "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.",

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

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

year = "2017",

month = mar,

day = "31",

doi = "10.1186/s12864-017-3620-y",

language = "English",

volume = "18",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

AU - Zuber, Verena

AU - Bettella, Francesco

AU - Witoelar, Aree

AU - Andreassen, Ole A.

AU - Mills, Ian G.

AU - Urbanucci, Alfonso

AU - Eeles, Rosalind

AU - Easton, Doug

AU - Kote-Jarai, Zsofia

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham G.

AU - Wiklund, Fredrik

AU - Gronberg, Henrik

AU - Haiman, Christopher A.

AU - Schleutker, Johanna

AU - Weischer, Maren

AU - Travis, Ruth C.

AU - Neal, David

AU - Pharoah, Paul

AU - Khaw, Kay Tee

AU - Stanford, Janet L.

AU - Blot, William J.

AU - Thibodeau, Stephen

AU - Maier, Christiane

AU - Kibel, Adam S.

AU - Cybulski, Cezary

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Park, Jong

AU - Kaneva, Radka

AU - Batra, Jyotsna

AU - Teixeira, Manuel R.

AU - Pandha, Hardev

AU - Chenevix-Trench, Georgia

AU - Humphreys, Manjeet

AU - Hung, R. J.

AU - Han, Y.

AU - Brennan, P.

AU - Bickeböller, H.

AU - Rosenberger, A.

AU - Houlston, R. S.

AU - Caporaso, N.

AU - Landi, M. T.

AU - Wu, X.

AU - Wang, Qin

AU - Bojesen, Stig E.

AU - Nielsen, Sune F.

AU - Nordestgaard, Borge G.

AU - the PRACTICAL Consortium, the COGS-CRUK GWAS, the BCAC Consortium, the TRICL Consortium

PY - 2017/3/31

Y1 - 2017/3/31

N2 - 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.

AB - 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.

KW - BRD4

KW - Breast cancer risk

KW - Chromatin

KW - Functional annotation

KW - Genome-wide association studies

KW - Prostate cancer risk

KW - Risk loci

KW - Schizophrenia

KW - SNPs

KW - Super-enhancer

U2 - 10.1186/s12864-017-3620-y

DO - 10.1186/s12864-017-3620-y

M3 - Journal article

C2 - 28359301

AN - SCOPUS:85016644651

SN - 1471-2164

VL - 18

JO - BMC Genomics

JF - BMC Genomics

M1 - 270

ER -

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

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