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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2838-2855
Number of pages18
JournalCancer Discovery
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2022

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint

Dive into the research topics of 'Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture'. Together they form a unique fingerprint.

Cite this