SPOP mutation leads to genomic instability in prostate cancer.

Gunther Boysen,Dennis Huang,Yariv Houvras,Sung-Suk Chae,Limei Xu,Davide Prandi,Clarisse Marotz,Paola Lecca,Andrea Sboner,Arun Dahija,Francesca Demichelis,Pengbo Zhou,Sagar Chhangawala,Mirjam Blattner,Julie Huang,Srilakshmi Nataraj,Christopher E Barbieri ,Johann S De Bono ,Liu D ,Mark A Rubin

doi:10.7554/elife.09207

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.

Highlights

Genomic instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many human cancers (Hanahan and Weinberg, 2011; Garraway and Lander, 2013)
To nominate somatic events associated with structural genomic rearrangements in clinically localized prostate cancer, we examined Whole genome sequencing (WGS) data from 55 treatment naive prostate cancers (Baca et al, 2013) (Figure 1A)
We investigated the role of SPOP in double strand break (DSB) repair using the well established DR-GFP and Pem1Ad2-EGFP reporter assays as functional readouts for homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively (Figure 4A,D) (Pierce et al, 1999; Seluanov et al, 2004)

Summary

Introduction

Genomic instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many human cancers (Hanahan and Weinberg, 2011; Garraway and Lander, 2013). Structural genomic rearrangements, including translocations (e.g., TMPRSS2-ERG) and copy number aberrations (e.g., 8q gain, 10q23/PTEN loss) are a key mechanism driving tumorigenesis (Visakorpi et al, 1995; Cher et al, 1996; Tomlins et al, 2005; Zhao et al, 2005; Liu et al, 2006; Demichelis et al, 2009; Beroukhim et al, 2010). Whole genome sequencing (WGS) has allowed an unprecedented insight into the alterations underlying cancer. WGS of treatment naive, clinically localized prostate cancer revealed a striking

Methods

Results

Conclusion