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Agglomerative Epigenetic Aberrations Are a Common Event in Human Breast Cancer

¹ Arizona Cancer Center, Departments of ² Pharmacology and Toxicology and ³ Surgery, University of Arizona, Tucson, Arizona; and ⁴ Institute of Plant Molecular Biology AS CR, Ceske Budejovice, Czech Republic

Requests for reprints: Bernard W. Futscher, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-4646; Fax: 520-626-4979; E-mail: bfutscher{at}azcc.arizona.edu.

Key Words: DNA methylation • epigenetic • breast cancer • CpG island • silencing

Changes in DNA methylation patterns are a common characteristic of cancer cells. Recent studies suggest that DNA methylation affects not only discrete genes, but it can also affect large chromosomal regions, potentially leading to LRES. It is unclear whether such long-range epigenetic events are relatively rare or frequent occurrences in cancer. Here, we use a high-resolution promoter tiling array approach to analyze DNA methylation in breast cancer specimens and normal breast tissue to address this question. We identified 3,506 cancer-specific differentially methylated regions (DMR) in human breast cancer with 2,033 being hypermethylation events and 1,473 hypomethylation events. Most of these DMRs are recurrent in breast cancer; 90% of the identified DMRs occurred in at least 33% of the samples. Interestingly, we found a nonrandom spatial distribution of aberrantly methylated regions across the genome that showed a tendency to concentrate in relatively small genomic regions. Such agglomerates of hypermethylated and hypomethylated DMRs spanned up to several hundred kilobases and were frequently found at gene family clusters. The hypermethylation events usually occurred in the proximity of the transcription start site in CpG island promoters, whereas hypomethylation events were frequently found in regions of segmental duplication. One example of a newly discovered agglomerate of hypermethylated DMRs associated with gene silencing in breast cancer that we examined in greater detail involved the protocadherin gene family clusters on chromosome 5 (PCDHA, PCDHB, and PCDHG). Taken together, our results suggest that agglomerative epigenetic aberrations are frequent events in human breast cancer. [Cancer Res 2008;68(20):8616–25]

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