title: High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients.
abstract: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient's family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan.
  
  
  
  Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics.
  
  
  
  Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P < 0.0001). 1 % of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14 % vs. 5 %, P = 0.03), 2) diagnosed at early-age irrespective of family history (28 % vs. 11 %, P = 0.0003), 3) had a family history of breast cancer (49 % vs. 12 %, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81 % vs. 28 %, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22-53) vs. 28 years (range 18-67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95 % CI 2.50-7.14; P < 0.0001).
  
  
  
  Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC.
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.|German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Heidelberg, Germany.
authors.forename: Muhammad Usman
authors.initials: MU
authors.lastname: Rashid
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Noor
authors.initials: N
authors.lastname: Muhammad
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Seerat
authors.initials: S
authors.lastname: Bajwa
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Saima
authors.initials: S
authors.lastname: Faisal
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tahseen
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.affiliation: Levine Cancer Institute (LCI), Charlotte, USA.
authors.forename: Asim
authors.initials: A
authors.lastname: Amin
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Asif
authors.initials: A
authors.lastname: Loya
authors.affiliation: German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Heidelberg, Germany. u.hamann@dkfz-heidelberg.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010154:Pakistan / Q000453:epidemiology; D015995:Prevalence; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor
keywords: BRCA1/2; Breast cancer; Germline mutations; Pakistan; Triple-negative breast cancer