Prevalence of BRCA mutations in an unselected population of triple‐negative breast cancer

Abstract

BACKGROUND: This study assessed BRCA1 and BRCA2 mutation prevalence in an unselected cohort of patients with triple-negative breast cancer (BC). METHODS: One hundred ninety-nine patients were enrolled. Triple negativity was defined as <1% estrogen and progesterone staining by immunohistochemistry and HER-2/neu not overexpressed by fluorescence in situ hybridization. Having given consent, patients had BRCA1 and BRCA2 full sequencing and large rearrangement analysis. Mutation prevalence was assessed among the triple-negative BC patients and the subset of patients without a family history of breast/ovarian cancer. Independent pathological review was completed on 50 patients. RESULTS: Twenty-one deleterious BRCA mutations were identified-13 in BRCA1 and 8 in BRCA2 (prevalence, 10.6%). In 153 patients (76.9%) without significant family history (first-degree or second-degree relatives with BC aged <50 years or ovarian cancer at any age), 8 (5.2%) mutations were found. By using prior National Comprehensive Cancer Network (NCCN) guidelines recommending testing for triple-negative BC patients aged <45 years, 4 of 21 mutations (19%) would have been missed. Two of 21 mutations (10%) would have been missed using updated NCCN guidelines recommending testing for triple-negative BC patients aged <60 years. CONCLUSIONS: The observed mutation rate was significantly higher (P ¼ .0005) than expected based on previously established prevalence tables among patients unselected for pathology. BRCA1 mutation prevalence was lower, and BRCA2 mutation prevalence was higher, than previously described. Additional mutation carriers would have met new NCCN testing guidelines, underscoring the value of the updated criteria. Study data suggest that by increasing the age limit to 65 years, all carriers would have been identified. Cancer 2012;118:2787-

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

“…This is a much higher percentage than the 10-20% seen in other studies of patients with TNBC unselected for family history. 7,8,15 Considering the results from both our diagnostic and research cohorts, we wondered whether the high prevalence of mutation c.4183C4T in the Zillertal and LIV region is associated with an increased incidence of cancer. Detailed regional data from the Tyrolean Cancer Registry confirmed an increased risk for breast and ovarian cancer especially in the region of Zillertal with SIRs of 1.23 for breast cancer below the age of 50 and 2.13 years for ovarian cancer below the age of 65 years.…”

“…Tumour characteristics (triple-negative breast cancer; TNBC) are also used for the identification of patients with a high probability of carrying a BRCA mutation. 7,8 Reduced costs of novel sequencing methods and better knowledge of the clinical relevance of alterations in BRCA1 and BRCA2 will increase the number of individuals eligible for sequence analysis, although some selection process will still remain necessary in the foreseeable future. Identification of common founder mutations in certain ethnicities allows integration of genetic testing strategies in the routine care of all cancer patients.…”

DNA repair, genome stability and cancer: a historical perspective

“…However the penetrance of such polymorphisms is weak and the clinical relevance of these to the overall cancer burden was unclear 30 . Subsequently several complex conditions in which cancer predisposition is a feature, such as Bloom's and Werner's syndromes, and Fanconi anaemia, have been shown to arise from genetic defects in DNA repair systems, as have subsets of familial breast, ovarian, prostate and pancreatic cancers [31][32][33][34][35][36] .…”

Low prevalence of germline PALB2 mutations in Australian triple‐negative breast cancer

“…Recent studies have shown that 20% of tumours classified as TNBC present with BRCA mutations. 4,5 Additionally, germline BRCA mutations are also overrepresented in TNBC patients, predominantly those with early-onset breast cancer. [6][7][8][9] This suggests a link between the BRCA-associated DNA repair pathway and TNBC.…”