title: Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities.
abstract: BACKGROUND
  Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas.
  
  
  METHODS
  A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry.
  
  
  RESULTS
  Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1.
  
  
  CONCLUSIONS
  High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. drjpress@telus.net
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Press
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Niki
authors.initials: N
authors.lastname: Boyd
authors.forename: Sean
authors.initials: S
authors.lastname: Young
authors.forename: Armelle
authors.initials: A
authors.lastname: Troussard
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Ridge
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Blood
authors.forename: Margaret
authors.initials: M
authors.lastname: Smith
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.forename: Yuker
authors.initials: Y
authors.lastname: Wang
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Miller
authors.forename: Doug
authors.initials: D
authors.lastname: Horsman
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human