BACKGROUND Despite 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. METHODS We 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. FINDINGS These 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. 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. FUNDING The National Cancer Institute of the National Institutes of Health, the V Foundation for Cancer Research and the New Jersey Commission for Cancer Research.

中文翻译：

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对人类肿瘤的综合蛋白质组学分析确定，ADNP是预后较差的高级浆液性卵巢癌中细胞周期进展的新型致癌介质。

背景技术尽管有毒副作用和有限的持久反应，目前用于高级浆液性卵巢癌（HGSOC）的护理标准治疗仍是基于铂/紫杉烷的化疗。考虑到在过去的几十年中，总体预后并未得到明显改善，因此迫切需要了解导致肿瘤发展和进展的潜在机制。方法我们利用对预后不良的基因表达特征（PPS）作为概念框架的HGSOC肿瘤的综合蛋白质组学分析，来分析来自TCGA（n = 488）和CPTAC（n = 169）研究的正交基因组和蛋白质组学数据。通过计算机分析鉴定出的基因在体外研究中得到评估，以证明其对增殖和细胞周期进程的影响。结果这些分析确定了在预后不良的肿瘤中DNA扩增和转录因子ADNP（活动性神经保护素同源盒）的过表达。验证研究证实了ADNP的预后能力，并考虑到ADNP表达与促增殖信号之间的联系，提示该蛋白具有致癌作用。体外研究证实，ADNP通过细胞周期检查点失调而成为细胞增殖的一种新型且必不可少的介质。解释我们通过计算机分析确定了在不良预后的HGSOC中ADNP被扩增和过表达，并证明了ADNP是HGSOC中的一种新颖且必不可少的致癌基因，它通过体外细胞周期检查点失调来介导增殖。资金美国国立卫生研究院国家癌症研究所