TY  - JOUR
AU  - Severson, TM
AU  - Peeters, J
AU  - Majewski, I
AU  - Michaut, M
AU  - Bosma, A
AU  - Schouten, PC
AU  - Chin, S-F
AU  - Pereira, B
AU  - Goldgraben, MA
AU  - Bismeijer, T
AU  - Kluin, RJC
AU  - Muris, JJF
AU  - Jirström, K
AU  - Kerkhoven, RM
AU  - Wessels, L
AU  - Caldas, C
AU  - Bernards, R
AU  - Simon, IM
AU  - Linn, S
Y2  - 2020/12/17
Y1  - 2015/10
SN  - 1574-7891
UR  - http://hdl.handle.net/11343/254782
AB  - 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.
LA  - eng
PB  - Wiley
T1  - BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential.
DO  - 10.1016/j.molonc.2015.04.011
IS  - Molecular Oncology
VL  - 9
IS  - 8
SP  - 1528-1538
L1  - /bitstream/handle/11343/254782/PMC5528786.pdf?sequence=1&isAllowed=y
ER  -