BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation

• Published in: Breast cancer research and treatment Vol. 167; no. 3; pp. 803 - 814
• Main Authors: Brianese, Rafael Canfield, Nakamura, Kivvi Duarte de Mello, Almeida, Fernanda Gabriella dos Santos Ramos de, Ramalho, Rodrigo Fernandes, Barros, Bruna Durães de Figueiredo, Ferreira, Elisa Napolitano e, Formiga, Maria Nirvana da Cruz, de Andrade, Victor Piana, de Lima, Vladmir Claudio Cordeiro, Carraro, Dirce Maria
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2018; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Age; Age of Onset; Aged; Aged, 80 and over; Analysis; Bisulfite; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Brief Report; Cancer genetics; Cancer research; Development and progression; Disease-Free Survival; DNA methylation; DNA Methylation - genetics; DNA repair; Female; Gene mutation; Genetic aspects; Germ-Line Mutation - genetics; Heterozygote; Humans; Investigations; Medicine; Medicine & Public Health; Methylation; Middle Aged; Mutation; Oncology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Promoter Regions, Genetic; Ribose; Sulfites; Survival; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - epidemiology; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors; Young Adult; Somatic; Mutation; Methylation; Germline; Triple-negative breast cancer; BRCA1
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4552-6

Purpose BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency. Methods Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening. A customized bisulfite next-generation sequencing approach was used for assessing BRCA1 promoter methylation status in tumor tissue. Results A total of 131 triple-negative cases were assessed, and germline pathogenic variants were detected in 13.0% of all cases and in 26% of cases diagnosed in young women. Most germline pathogenic variants (88.2%) occurred in the BRCA1 gene. BRCA1 promoter hypermethylation was detected in 20.6% of tumors; none of these tumors were in BRCA1/2 pathogenic variant carriers. BRCA1 impairment by either germline or somatic events was significantly more frequent in young women (55% in those ≤ 40 years; 33% in those 41–50 years; 22% in those > 50 years of age) and associated with better overall and disease-free survival rates in this group of patients. Conclusions BRCA1 deficiency was recurrent in early-onset triple-negative breast cancer in Brazilian patients and associated with improved survival. With the new treatment modalities being investigated, including poly (ADP-ribose)-polymerase (PARP) inhibitor therapy, our results suggest that a significant proportion of young women with this subtype of tumor might benefit from PARP inhibitor treatment, which warrants further investigation.