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

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

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

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

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

Peer reviewed: TrueFunder: Statistics NetherlandsFunder: Lower Saxonian Cancer SocietyFunder: Lise Boserup FundFunder: Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft; FundRef: http://dx.doi.org/10.13039/100018027Funder: Komen FoundationFunder: Claudia von Schilling Foundation for Breast Cancer ResearchFunder: Ligue Contre le Cancer; FundRef: http://dx.doi.org/10.13039/501100004099Funder: Sigrid Juselius FoundationFunder: Kuopion Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100004092Funder: Sheffield Experimental Cancer Medicine CentreFunder: Stockholm läns landsting; FundRef: http://dx.doi.org/10.13039/501100011727Funder: Department of Health and Human Services (USA)Funder: Stichting Tegen Kanker; FundRef: http://dx.doi.org/10.13039/501100005026Funder: David F. and Margaret T. Grohne Family Foundation; FundRef: http://dx.doi.org/10.13039/100009769Funder: Sundhed og Sygdom, Det Frie Forskningsråd; FundRef: http://dx.doi.org/10.13039/100008392Funder: Stavros Niarchos FoundationFunder: Institute of the Ruhr University BochumFunder: Institute of Cancer Research; FundRef: http://dx.doi.org/10.13039/501100000027Funder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328Funder: Institut National de la Santé et de la Recherche Médicale; FundRef: http://dx.doi.org/10.13039/501100001677Funder: Institute for Prevention and Occupational MedicineFunder: K.G. Jebsen Centre for Breast Cancer ResearchFunder: Research Centre for Genetic Engineering and BiotechnologyFunder: Robert and Kate Niehaus Clinical Cancer Genetics InitiativeFunder: Rudolf Bartling FoundationFunder: Karolinska Institutet; FundRef: http://dx.doi.org/10.13039/501100004047Funder: Robert Bosch Stiftung; FundRef: http://dx.doi.org/10.13039/501100001646Funder: Intramural Research Funds of the National Cancer Institute (USA)Funder: Intramural Research Program of the Division of Cancer Epidemiology and GeneticsFunder: Centre International de Recherche sur le Cancer; FundRef: http://dx.doi.org/10.13039/100008700Funder: Queensland Cancer FundFunder: Red Temática de Investigación Cooperativa en CáncerFunder: Intramural Research Program of the National Institutes of HealthFunder: National Health Service (UK)Funder: Ministerie van Volksgezondheid, Welzijn en Sport; FundRef: http://dx.doi.org/10.13039/501100002999Funder: Märit and Hans Rausings Initiative Against Breast CancerFunder: Associazione Italiana per la Ricerca sul Cancro; FundRef: http://dx.doi.org/10.13039/501100005010Funder: Fundación Científica Asociación Española Contra el Cáncer; FundRef: http://dx.doi.org/10.13039/501100002704Funder: Agence Nationale de la Recherche; FundRef: http://dx.doi.org/10.13039/501100001665Funder: Dutch Prevention Funds,Funder: Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du TravailFunder: American Cancer Society; FundRef: http://dx.doi.org/10.13039/100000048Funder: Dutch Zorg OnderzoekFunder: Alexander von Humboldt-Stiftung; FundRef: http://dx.doi.org/10.13039/100005156Funder: Ministerio de Economia y Competitividad (Spain)Funder: Against Breast Cancer; FundRef: http://dx.doi.org/10.13039/100013129Funder: Mutuelle Générale de l’Education NationaleFunder: Dietmar-Hopp Foundation,Funder: Division of Cancer Prevention, National Cancer Institute; FundRef: http://dx.doi.org/10.13039/100007316Funder: World Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/501100000321Funder: Genome QuébecFunder: National Cancer Research NetworkFunder: Berta Kamprad Foundation FBKSFunder: Biomedical Research Centre at Guy’s and St ThomasFunder: Genome Canada; FundRef: http://dx.doi.org/10.13039/100008762Funder: Friends of Hannover Medical SchoolFunder: Breast Cancer Research Foundation; FundRef: http://dx.doi.org/10.13039/100001006Funder: Breast Cancer NowFunder: UK National Institute for Health Research Biomedical Research CentreFunder: University of Crete; FundRef: http://dx.doi.org/10.13039/501100004429Funder: National Breast Cancer Foundation (Finland)Funder: European Regional Development Fund; FundRef: http://dx.doi.org/10.13039/501100008530Funder: National Breast Cancer Foundation (Australia)Funder: Directorate-General XII, Science, Research, and Development; FundRef: http://dx.doi.org/10.13039/501100012517Funder: Baden Württemberg Ministry of Science, Research and ArtsFunder: VicHealth; FundRef: http://dx.doi.org/10.13039/501100001231Funder: Victorian Breast Cancer Research Consortium.Funder: Finnish Cancer FoundationFunder: Fomento de la Investigación Clínica IndependienteFunder: the Cancer Biology Research Center (CBRC), Djerassi Oncology CenterFunder: Tel Aviv University Center for AI and Data ScienceFunder: University of OuluFunder: National Breast Cancer Foundation (JS)Funder: Safra Center for BioinformaticsFunder: Fondation de France, Institut National du CancerFunder: University of Utah; FundRef: http://dx.doi.org/10.13039/100007747Funder: National Cancer Center Research and Development Fund (Japan)Funder: Oak Foundation; FundRef: http://dx.doi.org/10.13039/100001275Funder: New South Wales Cancer CouncilFunder: North Carolina University Cancer Research FundFunder: Kreftforeningen; FundRef: http://dx.doi.org/10.13039/100008730Funder: Northern California Breast Cancer Family RegistryFunder: Institut Gustave RoussyFunder: Huntsman Cancer Institute, University of Utah; FundRef: http://dx.doi.org/10.13039/100010638Funder: Ovarian Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/100001282Funder: NIHR Oxford Biomedical Research Centre; FundRef: http://dx.doi.org/10.13039/501100013373Funder: Hellenic Health Foundation; FundRef: http://dx.doi.org/10.13039/501100018706Funder: Oulun Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100018949Funder: Helmholtz SocietyFunder: Herlev and Gentofte HospitalFunder: PSRSIIRI-701Funder: Helsinki University Hospital Research FundFunder: Cancer Council Victoria; FundRef: http://dx.doi.org/10.13039/501100000951Funder: National Research Council (Italy)Funder: Cancer Council Tasmania; FundRef: http://dx.doi.org/10.13039/501100001169Funder: Cancer Council Western Australia; FundRef: http://dx.doi.org/10.13039/501100001170Funder: Hamburger Krebsgesellschaft; FundRef: http://dx.doi.org/10.13039/100018515Funder: Gustav V Jubilee foundationFunder: National Program of Cancer RegistriesFunder: Cancer Council South Australia; FundRef: http://dx.doi.org/10.13039/501100000950Funder: Cancer Council NSW; FundRef: http://dx.doi.org/10.13039/501100001102Funder: Guy's & St. Thomas' NHS Foundation TrustFunder: Cancer Institute NSW; FundRef: http://dx.doi.org/10.13039/501100001171Funder: Cancer Foundation of Western AustraliaFunder: Netherlands Cancer Registry (NKR),Funder: Cancer Fund of North SavoBACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women