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Breast Cancer Res. 2014 Nov 22;16(6):466. doi: 10.1186/s13058-014-0466-y.

Identification by array comparative genomic hybridization of a new amplicon on chromosome 17q highly recurrent in BRCA1 mutated triple negative breast cancer.

Author information

1
Laboratory of Translational Oncology, Institute of Pathology and Genetics/ Grand Hôpital de Charleroi, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. sebastien.toffoli@ipg.be.
2
Laboratory of Translational Oncology, Institute of Pathology and Genetics/ Grand Hôpital de Charleroi, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. isabelle.bar@ipg.be.
3
Tumor Bank, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. fadi.abdulsater@ipg.be.
4
Department of Pathology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. paul.delree@ipg.be.
5
Department of Molecular Biology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. pascale.hilbert@ipg.be.
6
Department of Molecular Biology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. frederic.cavallin@ipg.be.
7
MdxHealth Inc 15279 Alton Parkway, Suite 100, Irvine, CA, 92618, USA. Fabrice.Moreau@mdxhealth.com.
8
MdxHealth Inc 15279 Alton Parkway, Suite 100, Irvine, CA, 92618, USA. wim.vancriekinge@mdxhealth.com.
9
Département de Biologie et de Pathologie, Institut Claudius Regaud, 20-24, Rue Pont St Pierre, Toulouse, 31052, France. lacroix.magali@claudiusregaud.fr.
10
Département d'Oncologie Médicale, Institut de Cancérologie de l'Ouest-René Gauducheau, Boulevard Jacques Monod, Saint-Herblain, Nantes, 44805, France. mario.campone@ico.unicancer.fr.
11
R&D UNICANCER, UNICANCER, Rue de Tolbiac 101, Paris, Cedex 13 75654, France. al-martin@unicancer.fr.
12
Département d'Oncologie Médicale, Institut Claudius Regaud, 20-24, Rue Pont St Pierre, Toulouse, 31300, France. roche.henri@claudiusregaud.fr.
13
Department of Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, Brussels, 1200, Belgium. Jean-Pascal.Machiels@uclouvain.be.
14
Service of Oncology-Hematology, Grand Hôpital de Charleroi, Grand'Rue, 3, Charleroi, 6000, Belgium. javier.carrasco@ghdc.be.
15
Service of Oncology-Hematology, Grand Hôpital de Charleroi, Grand'Rue, 3, Charleroi, 6000, Belgium. Jean_Luc.Canon@ghdc.be.

Abstract

INTRODUCTION:

Triple Negative Breast Cancers (TNBC) represent about 12% to 20% of all breast cancers (BC) and have a worse outcome compared to other BC subtypes. TNBC often show a deficiency in DNA double-strand break repair mechanisms. This is generally related to the inactivation of a repair enzymatic complex involving BRCA1 caused either by genetic mutations, epigenetic modifications or by post-transcriptional regulations. The identification of new molecular biomarkers that would allow the rapid identification of BC presenting a BRCA1 deficiency could be useful to select patients who could benefit from PARP inhibitors, alkylating agents or platinum-based chemotherapy.

METHODS:

Genomic DNA from 131 formalin-fixed paraffin-embedded (FFPE) tumors (luminal A and B, HER2+ and triple negative BC) with known BRCA1 mutation status or unscreened for BRCA1 mutation were analysed by array Comparative Genomic Hybridization (array CGH). One highly significant and recurrent gain in the 17q25.3 genomic region was analysed by fluorescent in situ hybridization (FISH). Expression of the genes of the 17q25.3 amplicon was studied using customized Taqman low density arrays and single Taqman assays (Applied Biosystems).

RESULTS:

We identified by array CGH and confirmed by FISH a gain in the 17q25.3 genomic region in 90% of the BRCA1 mutated tumors. This chromosomal gain was present in only 28.6% of the BRCA1 non-mutated TNBC, 26.7% of the unscreened TNBC, 13.6% of the luminal B, 19.0% of the HER2+ and 0% of the luminal A breast cancers. The 17q25.3 gain was also detected in 50% of the TNBC with BRCA1 promoter methylation. Interestingly, BRCA1 promoter methylation was never detected in BRCA1 mutated BC. Gene expression analyses of the 17q25.3 sub-region showed a significant over-expression of 17 genes in BRCA1 mutated TNBC (n = 15) as compared to the BRCA1 non mutated TNBC (n = 13).

CONCLUSIONS:

In this study, we have identified by array CGH and confirmed by FISH a recurrent gain in 17q25.3 significantly associated to BRCA1 mutated TNBC. Up-regulated genes in the 17q25.3 amplicon might represent potential therapeutic targets and warrant further investigation.

PMID:
25416589
PMCID:
PMC4303204
DOI:
10.1186/s13058-014-0466-y
[Indexed for MEDLINE]
Free PMC Article

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