title: Low levels of IGFBP7 expression in high-grade serous ovarian carcinoma is associated with patient outcome.
abstract: BACKGROUND
  Insulin-like growth factor binding protein 7 (IGFBP7) has been suggested to act as a tumour suppressor gene in various human cancers, yet its role in epithelial ovarian cancer (EOC) has not yet been investigated. We previously observed that IGFBP7 was one of several genes found significantly upregulated in an EOC cell line model rendered non-tumourigenic as consequence of genetic manipulation. The aim of the present study was to investigate the role of IGFBP7 in high-grade serous ovarian carcinomas (HGSC), the most common type of EOC.
  
  
  METHODS
  We analysed IGFBP7 gene expression in 11 normal ovarian surface epithelial cells (NOSE), 79 high-grade serous ovarian carcinomas (HGSC), and seven EOC cell lines using a custom gene expression array platform. IGFBP7 mRNA expression profiles were also extracted from publicly available databases. Protein expression was assessed by immunohistochemistry of 175 HGSC and 10 normal fallopian tube samples using tissue microarray and related to disease outcome. We used EOC cells to investigate possible mechanisms of gene inactivation and describe various in vitro growth effects of exposing EOC cell lines to human recombinant IGFBP7 protein and conditioned media.
  
  
  RESULTS
  All HGSCs exhibited IGFBP7 expression levels that were significantly (p = 0.001) lower than the mean of the expression value of NOSE samples and that of a whole ovary sample. IGFBP7 gene and protein expression were lower in tumourigenic EOC cell lines relative to a non-tumourigenic EOC cell line. None of the EOC cell lines harboured a somatic mutation in IGFBP7, although loss of heterozygosity (LOH) of the IGFBP7 locus and epigenetic methylation silencing of the IGFBP7 promoter was observed in two of the cell lines exhibiting loss of gene/protein expression. In vitro functional assays revealed an alteration of the EOC cell migration capacity. Protein expression analysis of HGSC samples revealed that the large majority of tumour cores (72.6%) showed low or absence of IGFBP7 staining and revealed a significant correlation between IGFBP7 protein expression and a prolonged overall survival (p = 0.044).
  
  
  CONCLUSIONS
  The low levels of IGFPB7 in HGSC relative to normal tissues, and association with survival are consistent with a purported role in tumour suppressor pathways.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada. karen.gambaro@mcgill.ca.|Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, H2X 0B9, Canada. karen.gambaro@mcgill.ca.
authors.forename: Karen
authors.initials: K
authors.lastname: Gambaro
authors.affiliation: Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada. michael.quinn@QIMRBerghofer.edu.au.|Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, H2X 0B9, Canada. michael.quinn@QIMRBerghofer.edu.au.
authors.forename: Michael C J
authors.initials: MC
authors.lastname: Quinn
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, H2X 0B9, Canada. ky.caceres@gmail.com.
authors.forename: Katia Y
authors.initials: KY
authors.lastname: Cáceres-Gorriti
authors.affiliation: Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada. rebecca.shapiro@gmail.com.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shapiro
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, H2X 0B9, Canada. diane.provencher.chum@ssss.gouv.qc.ca.|Department of Obstetric-Gynecology, Université de Montréal, Montreal, H2L 4M1, Canada. diane.provencher.chum@ssss.gouv.qc.ca.
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.affiliation: Department of Pathology, Université de Montréal, Montreal, H3C 3J7, Canada. kurosh.rahimi.chum@ssss.gouv.qc.ca.
authors.forename: Kurosh
authors.initials: K
authors.lastname: Rahimi
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montreal, H2X 0B9, Canada. anne-marie.mes-masson@umontreal.ca.|Department of Medicine, Université de Montréal, Montreal, H3C 3J7, Canada. anne-marie.mes-masson@umontreal.ca.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada. patricia.tonin@mcgill.ca.|The Research Institute of the McGill University Health Centre, Montreal, H4A 3J1, Canada. patricia.tonin@mcgill.ca.|Department of Medicine, McGill University, Montreal, H3G 1A4, Canada. patricia.tonin@mcgill.ca.|Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Site Glen Pavillion Block E, Cancer Research Program E026217 (cubicle E), Montreal, Quebec, H4A 3J1, Canada. patricia.tonin@mcgill.ca.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1