Abstract C25: The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression

Abstract

Abstract Prostate cancer (PCa) is a leading cause of cancer death and distinguishing life threatening tumors from indolent ones is a major challenge. The identification and characterization of genomic alterations associated with advanced disease may lead to the development of new markers of progression and more efficient therapeutic approaches. Array-CGH data have shown that gain of chromosome 16p13.3 to be associated with lymph node (LN) metastases of PCa, but this region remained uncharacterized. Our goal was to establish the prognostic value of 16p13.3 gain, and identify the cancer relevant genes residing within this region. In this study, we performed Fluorescence In Situ Hybridization (FISH) to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 transurethral resections of prostate (TURP) tissue samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathological parameters. We detected the gain in 5/10 LN metastases and 3/5 matched primary tumors, 3/9 CRPC samples, and 9/46 (20 %) primary tumors. In the latter set of samples, the 16p13.3 alteration was associated with high Gleason score (P=0.002) and elevated pre operative prostate specific antigen (PSA) levels (P=0.047). The levels of 16p13.3 gain were higher in LN metastasis and CRPC specimens compared to primary PCa (P>0.05). Chromosome mapping revealed a focal gain that spans PDPK1 encoding the 3-Phosphoinositide-dependent protein kinase-1 (PDK1). RNA interference-mediated knock down of PDK1 in three different PCa cell lines reduced cell motility without affecting growth and re-expressing PDK1 rescued motility (P>0.05). Our results support that the 16p13.3 gain is relevant to PCa progression and may represent an early marker of metastasis, since retrieved in primary PCa which is sampled by biopsies at time of diagnosis. PDK1 is implicated in PCa cell motility, a critical step for progression to metastasis. These findings provide further rationale for considering PDK1 as a target for cancer therapies and the development of new specific inhibitors of PDK1. Citation Format: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire. The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C25.