Genetic and epigenetic characterization of the BRCA1 gene in Brazilian women at-risk for hereditary breast cancer

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Felicio, Paula Silva ; Melendez, Matias Eliseo ; Rebolho Batista Arantes, Lidia Maria ; Kerr, Ligia Maria ; Carraro, Dirce Maria ; Grasel, Rebeca Silveira ; Campacci, Natalia ; Scapulatempo-Neto, Cristovam ; Fernandes, Gabriela Carvalho ; de Carvalho, Ana Carolina ; Palmero, Edenir Inez

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 2, p. 2850-2862, JAN 10 2017.
• Web of Science Citations: 0

Abstract

This study aimed to characterize women at-risk for hereditary BC regarding their clinical and molecular characteristics (mutation and methylation in the BRCA1 gene) and correlate the gene expression levels with histopathological, clinical and family history information. BRCA1 real time qPCR was performed to evaluate methylation status and gene expression. The study included 88 women grouped according to the BRCA1 mutational status: 23 BRCA1 mutated, 22 with a Variant of Unknown Significance (VUS) in BRCA1 and 43 BRCA1 WT. Most BRCA1 mutated tumors were triple negative (69.6%) and had histologic grade III (61.0%). Patients with VUS/WT BRCA1 were predominantly of luminal B subtype with histological grades I and II. Regarding the methylation profile, BRCA1 hypermethylation was observed in only two patients (both WT) and none had association with pathogenic BRCA1 mutation. In one patient methylation was present in both, tumor and normal tissues. Hypermethylated tumors had ductal histology, negativity for ER and occurred in < 50 years patients. Gene expression profile showed in all groups lower BRCA1 mRNA levels in tumor tissue compared to the adjacent breast tissue, thereby indicating the loss/decrease of gene function. No association was found between the levels of BRCA1 gene expression and family history of cancer. In summary, our findings suggested that methylation at the BRCA1 gene is not the ``second{''} event in the development of BC in patients with germline mutations in BRCA1 and, although rare, BRCA1 epimutations can constitute an explanation for a fraction of HBOC families. (AU)

• FAPESP's process: 13/24633-2 - Molecular characterization of at high risk families for hereditary breast cancer, negatives for BRCA1/BRCA2: looking for the BRCAx
• Grantee: Edenir Inêz Palmero
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/23277-8 - Molecular aspects involved in the development and progression of breast ductal carcinoma: investigation of carcinoma in situ progression and the role of BRCA1 mutation in the triple negative tumor
• Grantee: Dirce Maria Carraro
• Support Opportunities: Research Projects - Thematic Grants