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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Chromosomes, Human, Pair 6 / genetics
  • DNA Copy Number Variations / genetics
  • DNA Methylation / genetics*
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Neoplasm / genetics*
  • Genetic Association Studies*
  • Genome, Human / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kaplan-Meier Estimate
  • Meta-Analysis as Topic
  • Multivariate Analysis
  • Mutation / genetics
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism
  • Reproducibility of Results

Substances

  • RNA, Messenger
  • RECQL4 protein, human
  • RecQ Helicases

Grants and funding

Financial support for this study came from Inserm, Institut Paoli-Calmettes, and grants from Ligue Nationale Contre le Cancer (Label DB), GEFLUC (MC), Institut National du Cancer (ACI2007, AO2008, AO/R-TRANS09 «identification, caractérisation et validation clinique de nouvelles cibles cellulaires et moléculaires dans les cancers du sein de mauvais pronostic» IVOIRES (INCA)) and DGOS (SIRIC label: grant INCa-DGOS-Inserm 6038). LAK and IB were supported by a fellowship from the Franco-Algerian program of high level formation in France (PROFAS) and the Algerian government, respectively. MM was supported by a fellowship from the AVEROES European program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.