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Somatic copy number alterations by whole exome sequencing implicates YWHAZ and PTK2 in castration resistant prostate cancer

Menon, Roopika and Deng, Mario and Rüenauver, Kerstin and Kunze, Friedrich and Diana, Boehm and Vogel, Wenzel and Scheble, Veit and Fend, Falko and Kristiansen, Glen and Wernert, Nicolas and Oberbeckmann, Nicole and Biskup, Saskia and Rubin, Mark A. and Shaikhibrahim, Zaki and Perner, Sven (2013) Somatic copy number alterations by whole exome sequencing implicates YWHAZ and PTK2 in castration resistant prostate cancer. The Journal of Pathology.

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. In our study, we aimed at identifying novel genes involved in CRPC by assessing somatic copy number alterations (SCNA) using whole exome sequencing on CRPC and paired normal formalin fixed paraffin embedded (FFPE) samples by the SOLiD4 next generation sequencing platform. The CRPC and paired normal FFPE samples were sequenced and the data was further validated using fluorescence in-situ hybridization (FISH) on a PCa progression cohort consisting of 282 patients. Within the PCa progression cohort, YWHAZ was amplified in 3.7% of localized PCa, 25.4% of the lymph node metastases and notably in 48% of CRPC. PTK2 was amplified in 1.8% of localized PCa, 32.8% of lymph node metastases and 35% in CRPC. YWHAZ knockdown in PC-3 cells showed a significant decrease in proliferation and migration. Similarly, PTK2 inhibited cells significantly affected cell proliferation and migration. Our findings revealed that YWHAZ and PTK2 inhibition might delay the progression of the disease in CRPC patients harboring the amplification of these genes. Furthermore, our validated exome sequencing data proves that the identification of target candidates derived from FFPE tissue is a promising alternative for SCNA screening NGS technologies.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9117

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