PMID- 24114522
OWN - NLM
STAT- MEDLINE
DCOM- 20140414
LR  - 20220204
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 231
IP  - 4
DP  - 2013 Dec
TI  - Somatic copy number alterations by whole-exome sequencing implicates YWHAZ and 
      PTK2 in castration-resistant prostate cancer.
PG  - 505-16
LID - 10.1002/path.4274 [doi]
AB  - 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.
CI  - Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Menon, Roopika
AU  - Menon R
AD  - Department of Prostate Cancer Research, University Hospital of Bonn, Germany; 
      Institute of Pathology, University Hospital of Bonn, Germany.
FAU - Deng, Mario
AU  - Deng M
FAU - Ruenauver, Kerstin
AU  - Ruenauver K
FAU - Queisser, Angela
AU  - Queisser A
FAU - Peifer, Martin
AU  - Peifer M
FAU - Pfeifer, Martin
AU  - Pfeifer M
FAU - Offermann, Anne
AU  - Offermann A
FAU - Boehm, Diana
AU  - Boehm D
FAU - Vogel, Wenzel
AU  - Vogel W
FAU - Scheble, Veit
AU  - Scheble V
FAU - Fend, Falko
AU  - Fend F
FAU - Kristiansen, Glen
AU  - Kristiansen G
FAU - Wernert, Nicolas
AU  - Wernert N
FAU - Oberbeckmann, Nicole
AU  - Oberbeckmann N
FAU - Biskup, Saskia
AU  - Biskup S
FAU - Rubin, Mark A
AU  - Rubin MA
FAU - Adler, David
AU  - Adler D
FAU - Perner, Sven
AU  - Perner S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (TAE226)
RN  - 0 (YWHAZ protein, human)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
SB  - IM
EIN - J Pathol. 2014 May;233(1):101. Pfeifer, Martin [corrected to Peifer, Martin]
MH  - 14-3-3 Proteins/*genetics/metabolism
MH  - Cell Proliferation/drug effects
MH  - DNA Copy Number Variations/*genetics
MH  - DNA Mutational Analysis/methods
MH  - Exome/genetics
MH  - Focal Adhesion Kinase 1/antagonists & inhibitors/*genetics/metabolism
MH  - Gene Knockdown Techniques
MH  - Genetic Association Studies/methods
MH  - Humans
MH  - Male
MH  - Molecular Targeted Therapy/methods
MH  - Morpholines/pharmacology
MH  - Neoplasm Invasiveness
MH  - Neoplasm Proteins/genetics/metabolism
MH  - Orchiectomy
MH  - Paraffin Embedding
MH  - Prostatic Neoplasms/*genetics/metabolism/pathology/*surgery
MH  - Sequence Analysis, DNA/methods
MH  - Treatment Failure
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - castration-resistant prostate cancer
OT  - therapeutic targets: whole-exome sequencing
EDAT- 2013/10/12 06:00
MHDA- 2014/04/15 06:00
CRDT- 2013/10/12 06:00
PHST- 2013/04/22 00:00 [received]
PHST- 2013/09/10 00:00 [revised]
PHST- 2013/09/19 00:00 [accepted]
PHST- 2013/10/12 06:00 [entrez]
PHST- 2013/10/12 06:00 [pubmed]
PHST- 2014/04/15 06:00 [medline]
AID - 10.1002/path.4274 [doi]
PST - ppublish
SO  - J Pathol. 2013 Dec;231(4):505-16. doi: 10.1002/path.4274.