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

Autor: Severson TM; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Peeters J; Agendia NV, Amsterdam, The Netherlands., Majewski I; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Michaut M; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands., Bosma A; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands., Schouten PC; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Chin SF; CRUK Cambridge Institute, Cambridge, UK., Pereira B; CRUK Cambridge Institute, Cambridge, UK., Goldgraben MA; CRUK Cambridge Institute, Cambridge, UK., Bismeijer T; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands., Kluin RJ; Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands., Muris JJ; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Jirström K; Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden., Kerkhoven RM; Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands., Wessels L; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands., Caldas C; CRUK Cambridge Institute, Cambridge, UK., Bernards R; Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands., Simon IM; Agendia NV, Amsterdam, The Netherlands., Linn S; 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.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2015 Oct; Vol. 9 (8), pp. 1528-38. Date of Electronic Publication: 2015 May 07.
DOI: 10.1016/j.molonc.2015.04.011
Abstrakt: 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.
(Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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