Abstract B45: Amplification of ADNP and CEP250 promotes poor prognosis in high-grade serous ovarian cancer
Authors: Kubra Karagoz, Christen Khella, Michael L. Gatza
Journal: Clinical Cancer Research (2018)

Abstract High-grade serous ovarian cancer (HGSOC) is the most commonly diagnosed and most lethal subtype of gynecologic cancer. The poor prognosis associated with this disease stems from two major problems: diagnosis at later stages when ovarian cancer cells have metastasized to distant organs and intrinsic or developed resistance to primary platinum-taxane based therapies. Therefore, understanding the driver mechanisms of HGSOC is required to discover more effective therapeutic agents and identify potential drug targets. In this study, we applied an integrative multi-omics approach based on the use of a poor-prognostic gene expression signature as a conceptual framework to analyze orthogonal genomic and proteomic data from human ovarian tumors derived from the TCGA (n=489) and CPTAC (n=169) projects, including RNA expression, DNA copy number alterations, protein and phosphoprotein expression. In combination with data from a genome-wide RNA-mediated interference screen in human ovarian cancer cell lines, we also identified essential genetic drivers of poor prognosis. We identified genes in amplified regions that were positively correlated with poor-prognostic signature and showed an increased amplification frequency (q &amp;lt; 0.05). Then, we applied the poor-prognostic gene expression signatures to a panel of 29 ovarian cancer cell lines that had mRNA expression data and were also part of an RNAi proliferation screen in which a genome-wide shRNA library (~9,000 genes) had been used to identify essential genes. We used a negative Spearman rank correlation to identify essential genes in context of poor-prognosis signature. To prioritize these candidate genes, we next compared the results of these analyses and identified 128 genes that were uniquely essential for cell viability in ovarian cancer cell lines and that were amplified in the context of the poor-prognosis signature. In order to uncover underlying mechanisms in HGSOC, we examined relationships between the poor-prognostic gene expression signature score and proteins and phosphoprotein expression. We used a Spearman correlation comparing poor-prognostic signature score to protein expression level. The proteomic data obtained from different platforms that are analyses of reverse phase protein array (RPPA) (n=412) data including 141 proteins and 31 phosphoproteins and mass-spectrometry (MS)-based (n=169) data including 3330 proteins (n=169) and 2533 (n=69) phosphoproteins. Significant proteins derived from TCGA data enriched with biologic processes including cell cycle control (p=6.8E-11), cell proliferation and differentiation (P=1.9E-7) and inhibition of apoptosis (P=1.4E-5) and signaling pathways including ERBB signaling (P=3.0E-10), mTOR signaling (P=5.9E-9) and insulin signaling (P=2.9E-7) pathways. Significant proteins derived from CPTAC data played role in splicesome (P=2.4E-24), chromatin packaging and remodeling (P=3.7E-4), and cell cycle (P=1.2E-3). Next, we integrated all these analyses and determined that amplified essential genes including ADNP (Activity-Dependent Neuroprotective Protein), CEP250 (Centrosomal Nek2-Associated Protein 1), and MED1 (Mediator Complex Subunit 1) are also involved in significant phosphorylated proteins (P&amp;lt;0.05) correlated with poor-prognostic signature. We determined that amplification of ADNP (P = 0.0228; hazard ratio (HR), 0.84), CEP250 (P = 0.0346; HR, 0.82) predicted a significantly worse outcome in HGSOC patients, whereas MED1 amplification had no effect on patient survival (P = 0.0803). In conclusion, these analyses suggest that ADNP and CEP250 amplification are novel modulators of poor prognosis in ovarian cancer, and that these alterations are not only potential drivers of oncogenesis but also their associated pathways may represent novel therapeutic targets in HGSOC. Citation Format: Kubra Karagoz, Christen Khella, Michael L. Gatza. Amplification of ADNP and CEP250 promotes poor prognosis in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B45.