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Human Genetics

, Volume 138, Issue 10, pp 1091–1104 | Cite as

Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues

  • Hongjie Chen
  • Gleb Kichaev
  • Stephanie A. Bien
  • James W. MacDonald
  • Lu Wang
  • Theo K. Bammler
  • Paul Auer
  • Bogdan Pasaniuc
  • Sara LindströmEmail author
Original Investigation

Abstract

Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10−8 across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.

Notes

Acknowledgements

This work was supported by CA194393. The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie, de la Science et de l’Innovation du Québec’ through Genome Québec and Grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (2017). The Prostate cancer genome-wide association analyses are supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme Grant Agreement No. 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge Grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. EAO, DMK, and EMK acknowledge the Intramural Program of the National Human Genome Research Institute for their support. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for Elucidating Loci Involved in Prostate cancer Susceptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK Grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under Grant Agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 toE.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (Grant No. 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; http://www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (Grant No. K2010-70X-20430-04-3, 2014-2269). PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

439_2019_2041_MOESM1_ESM.tiff (693 kb)
Supplementary material 1 (TIFF 693 kb) Supplementary Fig. 1 Enrichment of breast cancer GWAS signals with p value < 10−8 in tissue-specific DHS, super enhancer and typical enhancer regions, after removing overlapped SNPs with corresponding annotation in breast cancer cell-line MCF-7
439_2019_2041_MOESM2_ESM.tiff (704 kb)
Supplementary material 2 (TIFF 703 kb) Supplementary Fig. 2 Enrichment of prostate cancer GWAS signals with p value < 10−8 in tissue-specific DHS, super enhancer and typical enhancer regions, after removing overlapped SNPs with corresponding annotation in prostate cancer cell-line LNCaP
439_2019_2041_MOESM3_ESM.xlsx (11.5 mb)
Supplementary material 3 (XLSX 11732 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of EpidemiologyUniversity of WashingtonSeattleUSA
  2. 2.Bioinformatics Interdepartmental ProgramUniversity of California Los AngelesLos AngelesUSA
  3. 3.Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  4. 4.Department of Environmental and Occupational Health SciencesUniversity of WashingtonSeattleUSA
  5. 5.Zilber School of Public HealthUniversity of Wisconsin–MilwaukeeMilwaukeeUSA
  6. 6.Departments of Human Genetics, and Pathology and Laboratory Medicine, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA

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