title: Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis.
abstract: Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer.
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia. catherine_emmanuel@wmi.usyd.edu.au
authors.forename: Catherine
authors.initials: C
authors.lastname: Emmanuel
authors.forename: Natalie
authors.initials: N
authors.lastname: Gava
authors.forename: Catherine
authors.initials: C
authors.lastname: Kennedy
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Balleine
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.forename: Gerard
authors.initials: G
authors.lastname: Wain
authors.forename: Alison
authors.initials: A
authors.lastname: Brand
authors.forename: Russell
authors.initials: R
authors.lastname: Hogg
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Paul R
authors.initials: PR
authors.lastname: Harnett
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D015331:Cohort Studies; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D030762:Estrous Cycle / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D009363:Neoplasm Proteins; C486061:NUAK2 protein, human; D017346:Protein Serine-Threonine Kinases