Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families

Clin Genet. 2008 Apr;73(4):338-45. doi: 10.1111/j.1399-0004.2008.00974.x. Epub 2008 Feb 26.

Abstract

While there are many reports in the literature of mutation testing of BRCA1 and BRCA2 in breast/ovarian cancer families, the question of which type of ovarian cancers are relevant still pertains. We have undertaken whole gene screening including multiple ligation-dependent probe amplification in an affected individual within 442 unrelated non-Jewish families containing at least one reported ovarian cancer diagnosed less than 50 years or at any age with family history of breast or ovarian cancer for mutations in BRCA1 and BRCA2. A total of 166 mutations were identified 110 (25%) in BRCA1 and 56 (13%) in BRCA2. In families without confirmation of ovarian diagnosis, the detection rate drops significantly. In families fulfilling Breast Cancer Linkage Consortium (BCLC) criteria with confirmed ovarian cancer cases, the mutation detection frequency was 80%. If only BCLC families with unconfirmed ovarian cancers were included, the detection rate dropped to 36% when a relevant ovarian cancer diagnosis was not confirmed. In BCLC families containing only one ovarian cancer, BRCA2 accounted for 45% of identified mutations. No mutations were identified in affected individuals with borderline or mucinous tumours. Detection rates dropped below the 10/20% international thresholds in a number of families with unconfirmed ovarian cancers. Borderline/mucinous pathology substantially reduces the likelihood of identifying a BRCA1/2 mutation. Strenuous efforts should be made to confirm ovarian pathology if the lack of confirmation or refuting the diagnosis would decrease a family's likelihood of mutation detection below screening thresholds. In the UK, a higher proportion of families harbour BRCA2 pathogenic mutations than predicted from previous studies.

MeSH terms

  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Breast Neoplasms / genetics
  • Female
  • Humans
  • Middle Aged
  • Mutation*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Ovary / pathology*
  • Probability
  • Retrospective Studies
  • Sensitivity and Specificity

Substances

  • BRCA1 Protein
  • BRCA2 Protein