Faculty Collaboration Database

Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues. Hum Genet 2019 Oct;138(10):1091-1104

Date

06/24/2019

Pubmed ID

31230194

Pubmed Central ID

PMC6745259

DOI

10.1007/s00439-019-02041-5

Scopus ID

2-s2.0-85067844927 (requires institutional sign-in at Scopus site)   6 Citations

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.

Author List

Chen H, Kichaev G, Bien SA, MacDonald JW, Wang L, Bammler TK, Auer P, Pasaniuc B, Lindström S

Author

Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Biomarkers, Tumor
Breast Neoplasms
Cell Line, Tumor
Computational Biology
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Male
Molecular Sequence Annotation
Organ Specificity
Prostatic Neoplasms
Regulatory Sequences, Nucleic Acid