Journal Article

BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential

Bismeijer, Tycho, Jirström, Karin, Peeters, Justine, Majewski, Ian, Pereira, Bernard, Bernards, René, Michaut, Magali, Goldgraben, Mae A., Kluin, Roelof J.C., Muris, Jettie J.F., Simon, Iris M., Schouten, Philip C., Kerkhoven, Ron M., Bosma, Astrid, Chin, Suet-Feung, Severson, Tesa M., Wessels, Lodewyk, Caldas, Carlos, Linn, Sabine

2015

Overview

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. •Triple negative breast cancers subdivide into 2 groups: BRCA1-like, non-BRCA1-like.•In a retrospective analysis, patients with BRCA1-like tumors have a worse outcome.•Mutation and gene expression patterns reveal potential therapy targets in subgroups.

• Publisher: Elsevier B.V,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 1-Phosphatidylinositol 3-kinase / Adult / Aged / Aged, 80 and over / BRCA1 / BRCA1 protein / Breast cancer / Cancer and Oncology / Cancer och onkologi / Cancer therapies / Cell cycle / Chemotherapy / Clinical Medicine / Comparative Genomic Hybridization / Copy number / Deoxyribonucleic acid / DNA / DNA Methylation / DNA Mutational Analysis / DNA repair / Epidermal growth factor / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes, BRCA1 / Genomes / Genomic instability / High-Throughput Nucleotide Sequencing / Homologous recombination / Humans / Kinases / Klinisk medicin / Medical and Health Sciences / Medical prognosis / Medicin och hälsovetenskap / Microarray Analysis / Middle Aged / Molecular Targeted Therapy - trends / Mutation / p53 Protein / Poly(ADP-ribose) polymerase / Prognosis / Promoter Regions, Genetic / Targeted therapy / Transcriptome / Triple negative breast cancer / Triple Negative Breast Neoplasms - classification / Triple Negative Breast Neoplasms - diagnosis / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - therapy / Tumor suppressor genes / Tumors