Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture-Reference-Cited by-同舟云学术

Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture

Published:2022-09-15 Issue:12 Volume:12 Page:2838-2855
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Yuan Jiapei¹²^ORCID,Houlahan Kathleen E.³⁴⁵⁶⁷^ORCID,Ramanand Susmita G.¹^ORCID,Lee Sora¹^ORCID,Baek GuemHee¹^ORCID,Yang Yang⁸⁹^ORCID,Chen Yong¹⁰^ORCID,Strand Douglas W.¹¹^ORCID,Zhang Michael Q.¹²¹³^ORCID,Boutros Paul C.³⁴⁵⁶¹⁴¹⁵^ORCID,Mani Ram S.¹¹¹¹⁶^ORCID

Affiliation:

1. 1Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.

2. 2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

3. 3Department of Human Genetics, University of California, Los Angeles, California.

4. 4Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.

5. 5Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

6. 6Vector Institute, Toronto, Ontario, Canada.

7. 7Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

8. 8The Province and Ministry Cosponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

9. 9Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.

10. 10Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, New Jersey.

11. 11Department of Urology, UT Southwestern Medical Center, Dallas, Texas.

12. 12Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Richardson, Texas.

13. 13MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, TNLIST/Department Automation, Tsinghua University, Beijing, China.

14. 14Department of Urology, University of California, Los Angeles, California.

15. 15Institute for Precision Health, University of California, Los Angeles, California.

16. 16Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.

Abstract

Abstract Prostate cancer is one of the most heritable human cancers. Genome-wide association studies have identified at least 185 prostate cancer germline risk alleles, most noncoding. We used integrative three-dimensional (3D) spatial genomics to identify the chromatin interaction targets of 45 prostate cancer risk alleles, 31 of which were associated with the transcriptional regulation of target genes in 565 localized prostate tumors. To supplement these 31, we verified transcriptional targets for 56 additional risk alleles using linear proximity and linkage disequilibrium analysis in localized prostate tumors. Some individual risk alleles influenced multiple target genes; others specifically influenced only distal genes while leaving proximal ones unaffected. Several risk alleles exhibited widespread germline–somatic interactions in transcriptional regulation, having different effects in tumors with loss of PTEN or RB1 relative to those without. These data clarify functional prostate cancer risk alleles in large linkage blocks and outline a strategy to model multidimensional transcriptional regulation. Significance: Many prostate cancer germline risk alleles are enriched in the noncoding regions of the genome and are hypothesized to regulate transcription. We present a 3D genomics framework to unravel risk SNP function and describe the widespread germline–somatic interplay in transcription control. This article is highlighted in the In This Issue feature, p. 2711

Funder

National Cancer Institute

Cancer Prevention and Research Institute of Texas

U.S. Department of Defense

Prostate Cancer Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-22-0027/3218038/cd-22-0027.pdf

Reference60 articles.