title: Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.
abstract: OBJECTIVE
  High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation.
  
  
  METHODS
  We describe gene expression and copy number analysis of two large cohorts of HGSC in which both germline and somatic inactivation of HRR has been measured.
  
  
  RESULTS
  BRCA1 disruptions were associated with the C2 (immunoreactive) molecular subtype of HGSC, characterized by intense intratumoral T-cell infiltration. We derived and validated a predictor of BRCA1 mutation or methylation status, but could not distinguish BRCA2 from wild-type tumors. DNA copy number analysis showed that cases with BRCA1 mutation were significantly associated with amplification both at 8q24 (frequencies: BRCA1 tumors 50%, BRCA2 tumors 32%, and wild-type tumors 9%) and regions of the X-chromosome specifically dysregulated in basal-like breast cancer (BLBC; BRCA1 62%, BRCA2 34%, and wild-type 35%). Tumors associated with BRCA1/BRCA2 mutations shared a negative association with amplification at 19p13 (BRCA1 0%, BRCA2 3%, and wild-type 20%) and 19q12 (BRCA1 6%, BRCA2 3%, and wild-type 29%).
  
  
  CONCLUSIONS
  The molecular differences between tumors associated with BRCA1 compared with BRCA2 mutations are in accord with emerging clinical and pathologic data and support a growing appreciation of the relationship between HGSC and BLBC.
authors: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Joshy
authors: J
authors: George
authors: Kathryn
authors: K
authors: Alsop
authors: Dariush
authors: D
authors: Etemadmoghadam
authors: Heather
authors: H
authors: Hondow
authors: Thomas
authors: T
authors: Mikeska
authors: Alexander
authors: A
authors: Dobrovic
authors: Anna
authors: A
authors: deFazio
authors: Gordon K
authors: GK
authors: Smyth
authors: Douglas A
authors: DA
authors: Levine
authors: Gillian
authors: G
authors: Mitchell
authors: David D
authors: DD
authors: Bowtell
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D002888:Chromosomes, Human, Pair 19; D002898:Chromosomes, Human, Pair 8; D041321:Chromosomes, Human, X; D056915:DNA Copy Number Variations; D004843:Epistasis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction