title: BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.
abstract: 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.
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Tesa M
authors.initials: TM
authors.lastname: Severson
authors.affiliation: Agendia NV, Amsterdam, The Netherlands.
authors.forename: Justine
authors.initials: J
authors.lastname: Peeters
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ian
authors.initials: I
authors.lastname: Majewski
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Magali
authors.initials: M
authors.lastname: Michaut
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: Bosma
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pereira
authors.affiliation: CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Mae A
authors.initials: MA
authors.lastname: Goldgraben
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Tycho
authors.initials: T
authors.lastname: Bismeijer
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Roelof J C
authors.initials: RJ
authors.lastname: Kluin
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jettie J F
authors.initials: JJ
authors.lastname: Muris
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ron M
authors.initials: RM
authors.lastname: Kerkhoven
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Agendia NV, Amsterdam, The Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pathology, University Medical Center Utrecht, The Netherlands. Electronic address: s.linn@nki.nl.
authors.forename: Sabine
authors.initials: S
authors.lastname: Linn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000639:trends*; D011401:Promoter Regions, Genetic; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000145:classification* / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy
keywords: BRCA1; Breast cancer; Genomic instability; Targeted therapy; Triple negative breast cancer