Stains
BRCA1

Author: Nat Pernick, M.D. (see Authors page)

Revised: 20 August 2015, last major update February 2013

Copyright: (c) 2003-2015, PathologyOutlines.com, Inc.

PubMed Search: BRCA1[title]

Definition / General
  • Breast cancer type 1 susceptibility protein
  • Tumor suppressor gene at 17q21; 220 kDa nuclear phosphoprotein, 1863 amino acids with 7.8 kb mRNA (OMIM 113705, Wikipedia)
Pathophysiology / Etiology
  • Interacts with RAD51; may facilitate homologous recombination in bypass of stalled replication forks
  • Loss of functional BRCA1 or BRCA2 leads to activation of p53, causing cell cycle arrest or apoptosis
  • If p53 if inactivated, proliferation results in progressive accumulation of DNA damage and increased frequency of malignancy
  • Overexpression suppresses estrogen receptor transactivation
Clinical Features
  • 185delAG and 5382insC mutations are common in Ashkenazi Jews
  • BRCA1 and BRCA2 mutations in Ashkenazi Jews have 2% prevalence vs. 0.1% of rest of population

    Breast:
  • Normally expressed at puberty and pregnancy
  • Interacts with cyclin dependent kinases; inhibits tumor growth in cell culture
  • Accounts for 5% (age < 40 years) to 1% (age 50-70 years) of breast cancer cases in general population
  • Patients with BRCA1 or BRCA2 mutation have 35%-80% lifetime risk of breast cancer by age 70
  • BRCA1 associated breast carcinomas are usually high grade, aneuploid with basal / myoepithelial phenotype of P-cadherin+ EGFR+ ER- PR- HER2- (Mod Pathol 2005;18:1305)
  • Higher risk of breast cancer with 300 T > G mutation
  • However, BRCA1 or BRCA2 mutation is also associated with medullary carcinoma of breast, which has more favorable prognosis

    Colon:
  • Relative risk of 4.0 for adenocarcinoma

    Ovary:
  • 30-60% lifetime risk of adenocarcinoma in women with mutations
  • Usually associated with serous cystadenocarcinoma; may be detectable only by thin sectioning and examination of entire ovary and fallopian tube (Am J Surg Pathol 2009;33:1878)
  • Often younger age and high stage
  • BRCA mutations cause 90% of hereditary cases of ovarian carcinomas, which account for 10% of all ovarian carcinomas (Hum Pathol 2005;36:861)

    Prostate:
  • Relative risk of 3.0 for adenocarcinoma
Uses by Pathologists
  • Immunostaining in high-grade serous ovarian carcinomas may be useful to stratify patients for germline genetic testing (loss of staining is abnormal, Am J Surg Pathol 2013;37:138)
Diagrams

Roles of BRCA1 and BRCA2 in DNA repair

Position on #17

Micro Images

High grade serous ovarian tumors with BRCA1 mutations

Positive Staining - Normal
  • Ovarian epithelium
Negative Staining
  • Loss of staining seen in high grade serous ovarian carcinoma