Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity

Victoria K. Hill, Christopher Ricketts, Ivan Bieche, Sophie Vacher, Dean Gentle, Cheryl Lewis, Eamonn R. Maher, Farida Latif

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P = 0.001), tumor relapse (P = 0.035), and lymph node metastasis (P = 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets.

Original languageEnglish (US)
Pages (from-to)2988-2999
Number of pages12
JournalCancer Research
Volume71
Issue number8
DOIs
StatePublished - Apr 15 2011

Fingerprint

CpG Islands
DNA Fingerprinting
DNA Methylation
Genome
Breast Neoplasms
Methylation
Genes
Neoplasms
Progesterone Receptors
Recurrence
Estrogen Receptors
Genomic Islands
Reverse Transcriptase Polymerase Chain Reaction
Epigenomics
Cluster Analysis
Real-Time Polymerase Chain Reaction
Biomarkers
Lymph Nodes
Neoplasm Metastasis
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. / Hill, Victoria K.; Ricketts, Christopher; Bieche, Ivan; Vacher, Sophie; Gentle, Dean; Lewis, Cheryl; Maher, Eamonn R.; Latif, Farida.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2988-2999.

Research output: Contribution to journalArticle

Hill, Victoria K. ; Ricketts, Christopher ; Bieche, Ivan ; Vacher, Sophie ; Gentle, Dean ; Lewis, Cheryl ; Maher, Eamonn R. ; Latif, Farida. / Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. In: Cancer Research. 2011 ; Vol. 71, No. 8. pp. 2988-2999.
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