title: Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
abstract: BACKGROUND
  Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH).
  
  
  METHODS
  Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines.
  
  
  RESULTS
  Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects.
  
  
  CONCLUSIONS
  The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.
authors.affiliation: Myriad Genetics Inc., Salt Lake City, UT, USA.
authors.forename: V
authors.initials: V
authors.lastname: Abkevich
authors.forename: K M
authors.initials: KM
authors.lastname: Timms
authors.forename: B T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: J
authors.initials: J
authors.lastname: Potter
authors.forename: M S
authors.initials: MS
authors.lastname: Carey
authors.forename: L A
authors.initials: LA
authors.lastname: Meyer
authors.forename: K
authors.initials: K
authors.lastname: Smith-McCune
authors.forename: R
authors.initials: R
authors.lastname: Broaddus
authors.forename: K H
authors.initials: KH
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: T V
authors.initials: TV
authors.lastname: Tran
authors.forename: D
authors.initials: D
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Iliev
authors.forename: S
authors.initials: S
authors.lastname: Jammulapati
authors.forename: L M
authors.initials: LM
authors.lastname: FitzGerald
authors.forename: T
authors.initials: T
authors.lastname: Krivak
authors.forename: J A
authors.initials: JA
authors.lastname: DeLoia
authors.forename: A
authors.initials: A
authors.lastname: Gutin
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.forename: J S
authors.initials: JS
authors.lastname: Lanchbury
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D015331:Cohort Studies; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D059767:Recombinational DNA Repair
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C448305:RAD51C protein, human