BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

Abstract

BackgroundGermline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC).MethodsIn this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria.ResultsA pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p ≤ 0.05) for 25 criteria; 14 of these had p ≤ 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer.ConclusionsThis is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil

“…Indeed, a recent study from Alemar et al . reported LGR data from 351 HBOC probands from the same Brazilian State where the previous cases harboring the 6 kb insertion were reported originally, and the BRCA1 6 kb insertion was not detected, suggesting a very low frequency of this LGR in probands with the HBOC phenotype 29 .…”

“…Knowledge about the germline mutational spectrum among Brazilian HBOC patients is limited. Only five studies have performed comprehensive BRCA mutation testing (using gene sequencing and LGR analysis) to date 25 – 29 , corresponding to only 1,041 individuals tested, among a Brazilian population of over 207 million people 30 . Most studies have focused on specific mutations, or screened only a few regions of BRCA1 and/or BRCA2 (summarized in the Supplementary Dataset).…”

Analysis of Heterozygous BRCA1 5382ins Founder Mutation in a Cohort of Egyptian Breast Cancer Female Patients Using Pyrosequencing Technique

“…On contrary, other studies found that triple negative BC was more common in BRCA mutations carriers, while triple positive tumors were more common in non-carriers. (Alemar et al, 2017;Chen et al, 2018). Furthermore, HER2-positive phenotype is a molecular subtype not frequently associated with BRCA deficiency (Maynes et al, 2010).…”

Cancer prevention – review paper

“…According to the recommendations of the diagnostic and therapeutic procedure in malignant neoplasms of 2013, screening consisting of mammography for women without clinical symptoms is the best method for the early detection of breast cancer. Assessment of the effectiveness of breast cancer prevention by mammographic screening showed a significant reduction in mortality from breast cancer (20-35%) among women aged 50-69 [122,123,124,125]. Mammography is most often used in the examination of breasts with a higher structural content of adipose tissue than glandular tissue, i.e.…”