title: Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling.
abstract: Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cornen
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guille
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: José
authors.initials: J
authors.lastname: Adélaïde
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France ; Biotoxicology Laboratory, Djillali Liabes University, Sidi-Bel-Abbès, Algeria.
authors.forename: Lynda
authors.initials: L
authors.lastname: Addou-Klouche
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Marie-Rose
authors.initials: MR
authors.lastname: Saade
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France ; Biochemistry and Molecular Biology Unit, Biology Dpt, Faculty of Sciences El Manar, Tunis, Tunisia.
authors.forename: Marwa
authors.initials: M
authors.lastname: Manai
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Carbuccia
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Ismahane
authors.initials: I
authors.lastname: Bekhouche
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Letessier
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Raynaud
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France ; Institut Paoli-Calmettes (IPC), Department of Biopathology, Marseille, France ; Aix-Marseille Université, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France ; Institut Paoli-Calmettes (IPC), Department of Biopathology, Marseille, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Jacquemier
authors.affiliation: Aix-Marseille Université, Marseille, France ; Inserm U1090, TAGC, Marseille, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.affiliation: UMR 944/7212 INSERM/CNRS/Université Paris 7, Hôpital St Louis, Paris, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: de The
authors.affiliation: Aix-Marseille Université, Marseille, France ; Institut Paoli-Calmettes (IPC), Department of Medical Oncology, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France ; Aix-Marseille Université, Marseille, France ; Institut Paoli-Calmettes (IPC), Department of Medical Oncology, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D056726:Genetic Association Studies; D015894:Genome, Human / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015201:Meta-Analysis as Topic; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D012333:RNA, Messenger; C506731:RECQL4 protein, human; D053484:RecQ Helicases