Integrative proteogenomic analyses of human tumours identifies ADNP as a novel oncogenic mediator of cell cycle progression in high-grade serous ovarian cancer with poor prognosis.

Kubra Karagoz,Pooja Khanna,Michael L Gatza,Gaurav A Mehta,Christen A Khella

doi:10.1016/j.ebiom.2019.11.009

Abstract

BackgroundDespite toxic side effects and limited durable response, the current standard-of-care treatment for high grade serous ovarian cancer (HGSOC) remains platinum/taxane-based chemotherapy. Given that the overall prognosis has not improved drastically over the past several decades, there is a critical need to understand the underlying mechanisms that lead to tumour development and progression.MethodsWe utilized an integrative proteogenomic analysis of HGSOC tumours applying a poor prognosis gene expression signature (PPS) as a conceptual framework to analyse orthogonal genomic and proteomic data from the TCGA (n = 488) and CPTAC (n = 169) studies. Genes identified through in silico analyses were assessed in vitro studies to demonstrate their impact on proliferation and cell cycle progression.FindingsThese analyses identified DNA amplification and overexpression of the transcription factor ADNP (Activity Dependent Neuroprotector Homeobox) in poorly prognostic tumours. Validation studies confirmed the prognostic capacity of ADNP and suggested an oncogenic role for this protein given the association between ADNP expression and pro-proliferative signalling. In vitro studies confirmed ADNP as a novel and essential mediator of cell proliferation through dysregulation of cell cycle checkpoints.InterpretationWe identified ADNP as being amplified and overexpressed in poor prognosis HGSOC in silico analyses and demonstrated that ADNP is a novel and essential oncogene in HGSOC which mediates proliferation through dysregulation of cell cycle checkpoints in vitro.FundingThe National Cancer Institute of the National Institutes of Health, the V Foundation for Cancer Research and the New Jersey Commission for Cancer Research.

Highlights

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States in 2019 [1]
These analyses demonstrated that poor prognosis may be associated with altered cell cycle progression, chromosome instability and proliferation as illustrated by the observed correlation between Poor Prognosis Signature (PPS) signature and RB LOH [33], RB Loss [34], CMYB [35], bMYB [36], and Chromosome Instability 70 gene signature (CIN70) [37] signatures as well as two independent proliferation signatures [38,39]
Given that ADNP was found to be an essential gene for cancer cell line viability in those cell lines with a gene expression profile associated with poor prognosis as illustrated in Fig. 3c (p = 0.02, r = À0.4) we examined the effect of ADNP on tumour cell proliferation and growth in order to begin to investigate the mechanisms by which ADNP affects high grade serous ovarian cancer (HGSOC) genesis and progression

Summary

Introduction

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States in 2019 [1]. HGSOC tumours express a relatively homogenous somatic or germline mutation profile and are characterized by TP53 mutations in >90% of tumours as well as frequent BRCA1 and BRCA2 mutations [3]. These mutations occur at a high frequency, HGSOC. Genes identified through in silico analyses were assessed in vitro studies to demonstrate their impact on proliferation and cell cycle progression. Interpretation: We identified ADNP as being amplified and overexpressed in poor prognosis HGSOC in silico analyses and demonstrated that ADNP is a novel and essential oncogene in HGSOC which mediates proliferation through dysregulation of cell cycle checkpoints in vitro.

Methods

Results

Conclusion