Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer
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Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. / Zuber, Verena; Bettella, Francesco; Witoelar, Aree; Andreassen, Ole A.; Mills, Ian G.; Urbanucci, Alfonso; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A.; Schleutker, Johanna; Weischer, Maren; Travis, Ruth C.; Neal, David; Pharoah, Paul; Khaw, Kay Tee; Stanford, Janet L.; Blot, William J.; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S.; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R.; Pandha, Hardev; Chenevix-Trench, Georgia; Humphreys, Manjeet; Hung, R. J.; Han, Y.; Brennan, P.; Bickeböller, H.; Rosenberger, A.; Houlston, R. S.; Caporaso, N.; Landi, M. T.; Wu, X.; Wang, Qin; Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Borge G.; the PRACTICAL Consortium, the COGS-CRUK GWAS, the BCAC Consortium, the TRICL Consortium.
In: BMC Genomics, Vol. 18, 270, 31.03.2017.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 18
JO - BMC Genomics
JF - BMC Genomics
SN - 1471-2164
M1 - 270
ER -
ID: 190432024