1. Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors
- Author
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Paul Guilhamon, Musaddeque Ahmed, Giacomo Grillo, Theodorus van der Kwast, Parisa Mazrooei, Andries M. Bergman, Mathieu Lupien, Nicholas Sinnott Armstrong, Ken Kron, Paul C. Boutros, Yanyun Zhu, Vincent Huang, Takafumi N. Yamaguchi, Michael Fraser, Housheng Hansen He, Robert G. Bristow, Wilbert Zwart, Stanley Zhou, Tahmid Mehdi, Tesa M. Severson, and Chemical Biology
- Subjects
Hepatocyte Nuclear Factor 3-alpha ,Male ,0301 basic medicine ,Cancer Research ,Somatic cell ,Computational biology ,Biology ,SDG 3 – Goede gezondheid en welzijn ,Genome ,03 medical and health sciences ,Prostate cancer ,Transactivation ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,single-nucleotide variant ,transcription regulators ,Transcription (biology) ,Cell Line, Tumor ,transcription factors ,medicine ,Humans ,noncoding mutations ,Epigenetics ,Transcription factor ,Homeodomain Proteins ,accessible chromatin ,epigenetics ,prostate tumor risk SNP ,Prostatic Neoplasms ,H3K27ac ,prostate cancer ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Cistrome ,cis-regulatory elements ,030220 oncology & carcinogenesis ,Mutation - Abstract
Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1, and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variants and somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulate in cistromes of master transcription regulators required for prostate cancer development.
- Published
- 2019
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