title: SPOP mutation leads to genomic instability in prostate cancer.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.|Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom.|The Royal Marsden, London, United Kingdom.
authors.forename: Gunther
authors.initials: G
authors.lastname: Boysen
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York, United States.|Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, United States.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Barbieri
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prandi
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Blattner
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Chae
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Arun
authors.initials: A
authors.lastname: Dahija
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Nataraj
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Marotz
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Limei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lecca
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, United States.|HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chhangawala
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York, United States.|HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States.
authors.forename: Deli
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.|HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States.|Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom.|The Royal Marsden, London, United Kingdom.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.|HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States.|Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, United States.|Department of Medicine, Weill Cornell Medical College, New York, United States.
authors.forename: Yariv
authors.initials: Y
authors.lastname: Houvras
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York, United States.|Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, United States.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.|Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency*; D011471:Prostatic Neoplasms / Q000473:pathology*; D012097:Repressor Proteins / Q000172:deficiency*; D043743:Ubiquitin-Protein Ligase Complexes; D015027:Zebrafish
chemical_list: D009153:Mutagens; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes
keywords: DNA repair; SPOP; cancer genomics; cell biology; human; human biology; medicine; mouse; prostate cancer; zebrafish