title: The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.
abstract: BACKGROUND
  BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms.
  
  
  METHODS
  Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups.
  
  
  RESULTS
  Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92).
  
  
  CONCLUSIONS
  BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.
authors.affiliation: Gynecologic Medical Oncology Service.
authors.forename: J L
authors.initials: JL
authors.lastname: Meisel
authors.affiliation: Gynecologic Medical Oncology Service; Developmental Therapeutics, Department of Medicine; Weill Cornell Medical College, New York, USA. Electronic address: hymand@mskcc.org.
authors.forename: D M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Pathology.
authors.forename: K
authors.initials: K
authors.lastname: Garg
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Gynecology Service, Department of Surgery.
authors.forename: F
authors.initials: F
authors.lastname: Dao
authors.affiliation: Gynecology Service, Department of Surgery.
authors.forename: M
authors.initials: M
authors.lastname: Bisogna
authors.affiliation: Computational Biology Program.
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.affiliation: Computational Biology Program.
authors.forename: N D
authors.initials: ND
authors.lastname: Schultz
authors.affiliation: Gynecologic Medical Oncology Service; Weill Cornell Medical College, New York, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Grisham
authors.affiliation: Gynecology Service, Department of Surgery.
authors.forename: M
authors.initials: M
authors.lastname: Phillips
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: A
authors.initials: A
authors.lastname: Iasonos
authors.affiliation: Gynecologic Medical Oncology Service; Gynecology Service, Department of Surgery; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Weill Cornell Medical College, New York, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Kauff
authors.affiliation: Gynecology Service, Department of Surgery; Weill Cornell Medical College, New York, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Pathology; Weill Cornell Medical College, New York, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Gynecologic Medical Oncology Service; Developmental Therapeutics, Department of Medicine; Weill Cornell Medical College, New York, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Spriggs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic
keywords: BRCA1; biomarkers; genetic testing; hypermethylation; immunohistochemistry; ovarian cancer