Agglomerative epigenetic aberrations are a common event in human breast cancer.

TitleAgglomerative epigenetic aberrations are a common event in human breast cancer.
Publication TypeJournal Article
Year of Publication2008
AuthorsNovak P, Jensen T, Oshiro MM, Watts GS, Kim CJ, Futscher BW
JournalCancer Res
Volume68
Issue20
Pagination8616-25
Date Published2008 Oct 15
ISSN1538-7445
KeywordsBreast Neoplasms, Cadherins, Cell Line, Tumor, CpG Islands, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Homeodomain Proteins, Humans, Multigene Family, Repressor Proteins
Abstract

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.

DOI10.1158/0008-5472.CAN-08-1419
Alternate JournalCancer Res.
PubMed ID18922938
PubMed Central IDPMC2680223
Grant ListP30 CA023074 / CA / NCI NIH HHS / United States
P30CA023074 / CA / NCI NIH HHS / United States
P30ES06694 / ES / NIEHS NIH HHS / United States
T32 ES007091 / ES / NIEHS NIH HHS / United States
R01 CA065662-08 / CA / NCI NIH HHS / United States
P30 ES006694 / ES / NIEHS NIH HHS / United States
CA09213 / CA / NCI NIH HHS / United States
R33 CA091351 / CA / NCI NIH HHS / United States
T32 CA009213 / CA / NCI NIH HHS / United States
R01 CA065662 / CA / NCI NIH HHS / United States
R01CA65662 / CA / NCI NIH HHS / United States
ES007091 / ES / NIEHS NIH HHS / United States
R33CA0951 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
George Watts, Ph.D.