@article{12b16dcfae704bfbb0f2f4c322fdf04d,
title = "Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture",
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.",
author = "Jiapei Yuan and Houlahan, {Kathleen E.} and Ramanand, {Susmita G.} and Sora Lee and Guemhee Baek and Yang Yang and Yong Chen and Strand, {Douglas W.} and Zhang, {Michael Q.} and Boutros, {Paul C.} and Mani, {Ram S.}",
note = "Funding Information: We thank James Malter, Diego Castrillon, and Ashish Kapoor for their insightful comments and discussions. R.S. Mani acknowledges funding support from National Cancer Institute (NCI)/NIH grant (R01CA245294), Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award (RP190454), US Department of Defense Prostate Cancer Research Program (PCRP) Impact Award (W81XWH-17-1-0675), and US Department of Defense Breakthrough Award (W81XWH-21-1-0114). K.E. Houlahan was supported by a Vanier Canada Graduate Scholarship. This work was also supported by the NIH/NCI under awards P30CA016042, U01CA214194, and U24CA248265 and by the Prostate Cancer Foundation Special Challenge Award to P.C. Boutros (Award ID #: 20CHAS01) made possible by the generosity of Mr. Larry Ruvo. The results described here are in part based on data generated by TCGA (http://cancergenome.nih.gov), managed by the NCI and the National Human Genome Research Institute (NHGRI). Funding Information: P.C. Boutros reports grants from the NCI, NIH, and the Prostate Cancer Foundation during the conduct of the study; other support from Sage Bionetworks, Intersect Diagnostics Inc., and BioSymetrics Inc. outside the submitted work; and a patent for germline determinants of prostate cancer aggression pending and a patent for ger-mline determinants of somatic mutations pending. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",
year = "2022",
month = dec,
day = "1",
doi = "10.1158/2159-8290.CD-22-0027",
language = "English (US)",
volume = "12",
pages = "2838--2855",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}