title: Identification by array comparative genomic hybridization of a new amplicon on chromosome 17q highly recurrent in BRCA1 mutated triple negative breast cancer.
abstract: BACKGROUND
  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.
authors.affiliation: Laboratory of Translational Oncology, Institute of Pathology and Genetics/ Grand Hôpital de Charleroi, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. sebastien.toffoli@ipg.be.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Toffoli
authors.affiliation: Laboratory of Translational Oncology, Institute of Pathology and Genetics/ Grand Hôpital de Charleroi, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. isabelle.bar@ipg.be.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bar
authors.affiliation: Tumor Bank, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. fadi.abdulsater@ipg.be.
authors.forename: Fadi
authors.initials: F
authors.lastname: Abdel-Sater
authors.affiliation: Department of Pathology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. paul.delree@ipg.be.
authors.forename: Paul
authors.initials: P
authors.lastname: Delrée
authors.affiliation: Department of Molecular Biology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. pascale.hilbert@ipg.be.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hilbert
authors.affiliation: Department of Molecular Biology, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, Gosselies, 6041, Belgium. frederic.cavallin@ipg.be.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cavallin
authors.affiliation: MdxHealth Inc 15279 Alton Parkway, Suite 100, Irvine, CA, 92618, USA. Fabrice.Moreau@mdxhealth.com.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moreau
authors.affiliation: MdxHealth Inc 15279 Alton Parkway, Suite 100, Irvine, CA, 92618, USA. wim.vancriekinge@mdxhealth.com.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.affiliation: Département de Biologie et de Pathologie, Institut Claudius Regaud, 20-24, Rue Pont St Pierre, Toulouse, 31052, France. lacroix.magali@claudiusregaud.fr.
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: R&D UNICANCER, UNICANCER, Rue de Tolbiac 101, Paris, Cedex 13 75654, France. al-martin@unicancer.fr.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Martin
authors.affiliation: Département d'Oncologie Médicale, Institut Claudius Regaud, 20-24, Rue Pont St Pierre, Toulouse, 31300, France. roche.henri@claudiusregaud.fr.
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.affiliation: Department of Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, Brussels, 1200, Belgium. Jean-Pascal.Machiels@uclouvain.be.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Service of Oncology-Hematology, Grand Hôpital de Charleroi, Grand'Rue, 3, Charleroi, 6000, Belgium. javier.carrasco@ghdc.be.
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.affiliation: Service of Oncology-Hematology, Grand Hôpital de Charleroi, Grand'Rue, 3, Charleroi, 6000, Belgium. Jean_Luc.Canon@ghdc.be.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Canon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human