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PLoS One. 2014 Jan 9;9(1):e81843. doi: 10.1371/journal.pone.0081843. eCollection 2014.

Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling.

Author information

  • 1Marseille Cancer Research Center, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Equipe labellisée Ligue Contre le Cancer, Marseille, France.
  • 2Marseille 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.
  • 3Marseille 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.
  • 4Marseille 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.
  • 5Marseille 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.
  • 6Aix-Marseille Université, Marseille, France ; Inserm U1090, TAGC, Marseille, France.
  • 7UMR 944/7212 INSERM/CNRS/Université Paris 7, Hôpital St Louis, Paris, France.
  • 8Aix-Marseille Université, Marseille, France ; Institut Paoli-Calmettes (IPC), Department of Medical Oncology, Marseille, France.
  • 9Marseille 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.

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.

PMID:
24416132
[PubMed - indexed for MEDLINE]
PMCID:
PMC3886975
Free PMC Article
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