Breast Cancer Research and Treatment

, Volume 167, Issue 3, pp 803–814 | Cite as

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

  • Rafael Canfield Brianese
  • Kivvi Duarte de Mello Nakamura
  • Fernanda Gabriella dos Santos Ramos de Almeida
  • Rodrigo Fernandes Ramalho
  • Bruna Durães de Figueiredo Barros
  • Elisa Napolitano e Ferreira
  • Maria Nirvana da Cruz Formiga
  • Victor Piana de Andrade
  • Vladmir Claudio Cordeiro de Lima
  • Dirce Maria Carraro
Brief Report



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.


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.


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.


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.


Triple-negative breast cancer BRCA1 Mutation Methylation Germline Somatic 



The authors are grateful to all patients for donating their biological samples for scientific research. We also thank Dr. Vinicius Fernando Calsavara for assistance with the statistical analysis and the A. C. Camargo Institutional Biobank for providing the DNA samples for the study.

Compliance with ethical standards

Conflict interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed involving human participants were in accordance with the ethical standards of the A. C. Camargo Cancer Center Research Ethics Committee (Number 1746/13) and with the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from all patients of the study, who signed the informed consent allowing the use of their biological material, donated for our Biobank, for scientific projects, and for data publication. The A. C. Camargo Cancer Center Biobank has approval of the National Ethical Committee under number B-001.

Supplementary material

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Supplementary material 1 (DOC 355 kb)
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Supplementary material 5 (TIFF 18368 kb)


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Rafael Canfield Brianese
    • 1
  • Kivvi Duarte de Mello Nakamura
    • 1
  • Fernanda Gabriella dos Santos Ramos de Almeida
    • 1
  • Rodrigo Fernandes Ramalho
    • 1
  • Bruna Durães de Figueiredo Barros
    • 1
  • Elisa Napolitano e Ferreira
    • 1
  • Maria Nirvana da Cruz Formiga
    • 2
    • 3
  • Victor Piana de Andrade
    • 4
  • Vladmir Claudio Cordeiro de Lima
    • 3
  • Dirce Maria Carraro
    • 1
  1. 1.Laboratory of Genomics and Molecular BiologyCIPE - A. C. Camargo Cancer CenterSão PauloBrazil
  2. 2.Department of OncogeneticsA. C. Camargo Cancer CenterSão PauloBrazil
  3. 3.Department of Medical OncologyA. C. Camargo Cancer CenterSão PauloBrazil
  4. 4.Department of Anatomic PathologyA. C. Camargo Cancer CenterSão PauloBrazil

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