BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.
AuthorSeverson, TM; Peeters, J; Majewski, I; Michaut, M; Bosma, A; Schouten, PC; Chin, S-F; Pereira, B; Goldgraben, MA; Bismeijer, T; ...
Source TitleMolecular Oncology
University of Melbourne Author/sMajewski, Ian
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsSeverson, T. M., Peeters, J., Majewski, I., Michaut, M., Bosma, A., Schouten, P. C., Chin, S. -F., Pereira, B., Goldgraben, M. A., Bismeijer, T., Kluin, R. J. C., Muris, J. J. F., Jirström, K., Kerkhoven, R. M., Wessels, L., Caldas, C., Bernards, R., Simon, I. M. & Linn, S. (2015). BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.. Mol Oncol, 9 (8), pp.1528-1538. https://doi.org/10.1016/j.molonc.2015.04.011.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528786
Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern of genomic copy number aberrations that can be used to classify tumors as BRCA1-like or non-BRCA1-like. BRCA1 mutation, promoter methylation, BRCA1-like status and genome-wide expression data was determined for 112 TN breast cancer samples with long-term follow-up. Mutation status for 21 known DNA repair genes and PIK3CA was assessed. Gene expression and mutation frequency in BRCA1-like and non-BRCA1-like tumors were compared. Multivariate survival analysis was performed using the Cox proportional hazards model. BRCA1 germline mutation was identified in 10% of patients and 15% of tumors were BRCA1 promoter methylated. Fifty-five percent of tumors classified as BRCA1-like. The functions of genes significantly up-regulated in BRCA1-like tumors included cell cycle and DNA recombination and repair. TP53 was found to be frequently mutated in BRCA1-like (P < 0.05), while PIK3CA was frequently mutated in non-BRCA1-like tumors (P < 0.05). A significant association with worse prognosis was evident for patients with BRCA1-like tumors (adjusted HR = 3.32, 95% CI = 1.30-8.48, P = 0.01). TN tumors can be further divided into two major subgroups, BRCA1-like and non-BRCA1-like with different mutation and expression patterns and prognoses. Based on these molecular patterns, subgroups may be more sensitive to specific targeted agents such as PI3K or PARP inhibitors.
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