Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors

Cancer Cell. 2019 Dec 9;36(6):674-689.e6. doi: 10.1016/j.ccell.2019.10.005. Epub 2019 Nov 14.

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.

Keywords: H3K27ac; accessible chromatin; cis-regulatory elements; epigenetics; noncoding mutations; prostate cancer; prostate tumor risk SNP; single-nucleotide variant; transcription factors; transcription regulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Male
  • Mutation / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Up-Regulation / genetics

Substances

  • HOXB13 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Homeodomain Proteins