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Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 18 February 2013, last major update February 2013
Copyright: (c) 2002-2013, PathologyOutlines.com, Inc.


● 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)


● 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

● 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

● Relative risk of 4.0 for adenocarcinoma

● 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)

● 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)


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

End of Stains > BRCA1

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