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

Jiapei Yuan; Kathleen E Houlahan; Susmita G Ramanand; Sora Lee; GuemHee Baek; Yang Yang; Yong Chen; Douglas W Strand; Michael Q Zhang; Paul C Boutros; Ram S Mani

doi:10.1158/2159-8290.CD-22-0027

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

Cancer Discov. 2022 Dec 2;12(12):2838-2855. doi: 10.1158/2159-8290.CD-22-0027.

Authors

Jiapei Yuan^{1

2}, Kathleen E Houlahan^{3

4

5

6

7}, Susmita G Ramanand¹, Sora Lee¹, GuemHee Baek¹, Yang Yang^{8

9}, Yong Chen¹⁰, Douglas W Strand¹¹, Michael Q Zhang^{12

13}, Paul C Boutros^{3

4

5

6

14

15}, Ram S Mani^{1

11

16}

Affiliations

¹ Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
² State 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 Department of Human Genetics, University of California, Los Angeles, California.
⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
⁶ Vector Institute, Toronto, Ontario, Canada.
⁷ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁸ The 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 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
¹⁰ Department of Molecular and Cellular Biosciences, Rowan University, Glassboro, New Jersey.
¹¹ Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
¹² Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Richardson, Texas.
¹³ MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, TNLIST/Department Automation, Tsinghua University, Beijing, China.
¹⁴ Department of Urology, University of California, Los Angeles, California.
¹⁵ Institute for Precision Health, University of California, Los Angeles, California.
¹⁶ Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Alleles
Genome-Wide Association Study*
Genomics / methods
Germ Cells / pathology
Humans
Male
Mutation
Polymorphism, Single Nucleotide
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding