SPOP mutation leads to genomic instability in prostate cancer. Academic Article uri icon

Overview

abstract

  • Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.

publication date

  • September 16, 2015

Research

keywords

  • Genomic Instability
  • Nuclear Proteins
  • Prostatic Neoplasms
  • Repressor Proteins

Identity

PubMed Central ID

  • PMC4621745

Scopus Document Identifier

  • 84945923475

Digital Object Identifier (DOI)

  • 10.1002/pros.20158

PubMed ID

  • 26374986

Additional Document Info

volume

  • 4