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

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 8, n. 2, p. 2850-2862, JAN 10 2017.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/24633-2 - Caracterização molecular de famílias de alto risco para câncer de mama hereditário, negativas para mutações nos genes BRCA1/BRCA2: à procura do BRCAx
• Beneficiário: Edenir Inêz Palmero
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/23277-8 - Aspectos moleculares envolvidos no risco, desenvolvimento e progressão do carcinoma ductal de mama: busca de novos genes de susceptibilidade e investigação da progressão do carcinoma in situ e do papel da mutação em BRCA1 no tumor triplo negativo
• Beneficiário: Dirce Maria Carraro
• Linha de fomento: Auxílio à Pesquisa - Temático