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

Severson, Tesa M; Peeters, Justine; Majewski, Ian; Michaut, Magali; Bosma, Astrid; Schouten, Philip C; Chin, Suet-Feung; Pereira, Bernard; Goldgraben, Mae A and Bismeijer, Tycho, et al. (2015) In Molecular Oncology 9(8). p.1528-1538
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... (More)
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. (Less)
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Molecular Oncology
volume
9
issue
8
pages
1528 - 1538
publisher
Elsevier
external identifiers
  • pmid:26004083
  • wos:000362308500003
  • scopus:84942193303
ISSN
1574-7891
DOI
10.1016/j.molonc.2015.04.011
language
English
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yes
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a9e7d4bc-231c-4f64-95e2-a4137c9ceff2 (old id 5442486)
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http://www.ncbi.nlm.nih.gov/pubmed/26004083?dopt=Abstract
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2015-06-05 12:55:53
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2017-11-12 03:14:42
@article{a9e7d4bc-231c-4f64-95e2-a4137c9ceff2,
  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 &lt; 0.05), while PIK3CA was frequently mutated in non-BRCA1-like tumors (P &lt; 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.},
  author       = {Severson, Tesa M and Peeters, Justine and Majewski, Ian and Michaut, Magali and Bosma, Astrid and Schouten, Philip C and Chin, Suet-Feung and Pereira, Bernard and Goldgraben, Mae A and Bismeijer, Tycho and Kluin, Roelof J C and Muris, Jettie J F and Jirström, Karin and Kerkhoven, Ron M and Wessels, Lodewyk and Caldas, Carlos and Bernards, René and Simon, Iris M and Linn, Sabine},
  issn         = {1574-7891},
  language     = {eng},
  number       = {8},
  pages        = {1528--1538},
  publisher    = {Elsevier},
  series       = {Molecular Oncology},
  title        = {BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.},
  url          = {http://dx.doi.org/10.1016/j.molonc.2015.04.011},
  volume       = {9},
  year         = {2015},
}