title: Somatic copy number alterations by whole-exome sequencing implicates YWHAZ and PTK2 in castration-resistant prostate cancer.
abstract: Castration-resistant prostate cancer (CRPC) is the most aggressive form of prostate cancer (PCa) and remains a significant therapeutic challenge. The key to the development of novel therapeutic targets for CRPC is to decipher the molecular alterations underlying this lethal disease. The aim of our study was to identify therapeutic targets for CRPC by assessing somatic copy number alterations (SCNAs) by whole-exome sequencing on five CRPC/normal paired formalin-fixed paraffin-embedded (FFPE) samples, using the SOLiD4 next-generation sequencing (NGS) platform. Data were validated using fluorescence in situ hybridization (FISH) on a PCa progression cohort. PTK2 and YWHAZ amplification, mRNA and protein expression were determined in selected PCa cell lines. Effects of PTK2 inhibition using TAE226 inhibitor and YWHAZ knock-down on cell proliferation and migration were tested in PC3 cells in vitro. In a larger validation cohort, the amplification frequency of YWHAZ was 3% in localized PCa and 48% in CRPC, whereas PTK2 was amplified in 1% of localized PCa and 35% in CRPC. YWHAZ knock-down and PTK2 inhibition significantly affected cell proliferation and migration in the PC3 cells. Our findings suggest that inhibition of YWHAZ and PTK2 could delay the progression of the disease in CRPC patients harbouring amplification of the latter genes. Furthermore, our validated whole-exome sequencing data show that FFPE tissue could be a promising alternative for SCNA screening using next-generation sequencing technologies.
authors.affiliation: Department of Prostate Cancer Research, University Hospital of Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Germany.
authors.forename: Roopika
authors.initials: R
authors.lastname: Menon
authors.forename: Mario
authors.initials: M
authors.lastname: Deng
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rüenauver
authors.forename: Angela
authors.initials: A
authors.lastname: Queisser
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Martin
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Anne
authors.initials: A
authors.lastname: Offermann
authors.forename: Diana
authors.initials: D
authors.lastname: Boehm
authors.forename: Wenzel
authors.initials: W
authors.lastname: Vogel
authors.forename: Veit
authors.initials: V
authors.lastname: Scheble
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wernert
authors.forename: Nicole
authors.initials: N
authors.lastname: Oberbeckmann
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: David
authors.initials: D
authors.lastname: Adler
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009919:Orchiectomy; D016612:Paraffin Embedding; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D017422:Sequence Analysis, DNA / Q000379:methods; D017211:Treatment Failure; D014407:Tumor Cells, Cultured
chemical_list: D048948:14-3-3 Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; C524632:TAE226; C572235:YWHAZ protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: castration-resistant prostate cancer; therapeutic targets: whole-exome sequencing