Abstract 3875: NUAK2, a gene with a putative driver mutation in ovarian cancer, is regulated through the murine estrus cycle and loss is associated with worse outcome in ovarian cancer

Abstract

Abstract Molecular events leading to ovarian cancer are poorly understood but ovulatory hormones and a high number of lifetime ovulations increase risk. The most common histotype, serous ovarian cancer, is thought to arise from ovarian surface epithelium or inclusion cysts although recent evidence has implicated fallopian tube epithelium and other Müllerian tissues as potential sites of origin. The aim of this study was to identify genes that may play a critical role in the pathogenesis of ovarian cancer from candidates that we have previously identified as regulated during the murine estrus cycle in microdissected ovarian surface epithelium and matched oviduct. We examined estrus regulated gene profiles in normal mouse ovarian and oviduct epithelium for genes (i) differentially expressed in ovarian cancer compared to normal controls; (ii) with copy number aberration in ovarian cancer; and (iii) with reported mutation in solid tumors. We identified over 350 genes that are regulated in the normal mouse ovarian epithelium during the estrus cycle and dysregulated in cancer including four genes found to be mutated in various tumour types (Catalogue Of Somatic Mutations In Cancer) and around 50 genes that have copy number aberration in ovarian cancer (The Cancer Genome Atlas). A similar number of genes were regulated in the normal mouse oviduct epithelium during the estrus cycle and dysregulated in ovarian cancer including six that are mutated in various tumor types and around 35 with copy number aberration in ovarian cancer. Interestingly, there was very little similarity between the ovarian and oviduct epithelium gene lists with only 19 genes in common, however, pathway analysis revealed over-representation of genes involved in cell cycle, particularly the spindle assembly checkpoint, and extracellular matrix/cell adhesion in both lists. We identified NUAK family, SNF1-like kinase, 2 (NUAK2) as upregulated in ovarian epithelium during the proestrus phase of the murine estrus cycle, upregulated in ovarian cancer and with a candidate driver mutation for breast and ovarian cancer. Expression of NUAK2 was examined by immunohistochemistry in human ovary (n=10), fallopian tube (n=9), and ovarian cancer (n=119). This showed that NUAK2 expression was highest in fallopian tube, intermediate in OSE and lost in ∼20% of ovarian cancer cases. Kaplan-Meier curves with log-rank test revealed reduced expression of NUAK2 was significantly associated with reduced overall survival in ovarian cancer (p<0.04). Future work involves functional analysis of key genes, including NUAK2, in human cell lines. Defining genes that are activated in normal ovarian and oviduct epithelial cells in the course of ovulation that are also dysregulated in cancer has identified a number of molecular pathways and novel candidate genes that may contribute to the development of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3875. doi:10.1158/1538-7445.AM2011-3875