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Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms

Anamay Shetty, Ji-Heui Seo, Connor A. Bell, Edward P. O’Connor, Mark Pomerantz, Matthew L. Freedman, Alexander Gusev
doi: https://doi.org/10.1101/2021.06.02.446619
Anamay Shetty
1University of Cambridge, Cambridge, UK
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Ji-Heui Seo
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
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Connor A. Bell
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Edward P. O’Connor
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Mark Pomerantz
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
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Matthew L. Freedman
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
4The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
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Alexander Gusev
2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
4The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
5Division of Genetics, Brigham & Women’s Hospital, Boston, MA, USA
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  • For correspondence: alexander_gusev@dfci.harvard.edu
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Abstract

Background Genome-wide association studies of prostate cancer have identified >250 significant risk loci, but the causal variants and mechanisms for these loci remain largely unknown. Here, we sought to identify and characterize risk harboring regulatory elements by integrating epigenomes from primary prostate tumor and normal tissues of 27 patients across the H3K27ac, H3K4me3, and H3K4me2 histone marks and FOXA1 and HOXB13 transcription factors.

Results We identified 7,371 peaks with significant allele-specificity (asQTL peaks). Showcasing their relevance to prostate cancer risk, H3K27ac T-asQTL peaks were the single annotation most enriched for prostate cancer GWAS heritability (40x), significantly higher than corresponding non-asQTL H3K27ac peaks (14x) or coding regions (14x). Surprisingly, fine-mapped GWAS risk variants were most significantly enriched for asQTL peaks observed in tumors, including asQTL peaks that were differentially imbalanced with respect to tumor-normal states. These data pinpointed putative causal regulatory elements at 20 GWAS loci, of which 11 were detected only in the tumor samples. More broadly, tumor-specific asQTLs were enriched for expression QTLs in benign tissues as well as accessible regions found in stem cells, supporting a hypothesis where some germline variants become reactivated during/after transformation and can be captured by epigenomic profiling of the tumor.

Conclusion Our study demonstrates the power of allele-specificity in chromatin signals to uncover GWAS mechanisms, highlights the relevance of tumor-specific regulation in the context of cancer risk, and prioritizes multiple loci for experimental follow-up.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 11, 2021.
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Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms
Anamay Shetty, Ji-Heui Seo, Connor A. Bell, Edward P. O’Connor, Mark Pomerantz, Matthew L. Freedman, Alexander Gusev
bioRxiv 2021.06.02.446619; doi: https://doi.org/10.1101/2021.06.02.446619
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Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms
Anamay Shetty, Ji-Heui Seo, Connor A. Bell, Edward P. O’Connor, Mark Pomerantz, Matthew L. Freedman, Alexander Gusev
bioRxiv 2021.06.02.446619; doi: https://doi.org/10.1101/2021.06.02.446619

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