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Hypomethylation of pericentromeric DNA in breast adenocarcinomas
1Department of Biochemistry, Tulane Medical School, New Orleans, LA 70112, USA.
Abstract:
Drug-induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric region instability, facial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocarcinoma. We found that almost half of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromatin adjacent to the centromere of chromosome 1 and is normally highly methylated. One of the 19 examined non-malignant breast tissues displaying fibrocystic changes was similarly hypomethylated in this satellite DNA. We also looked at an opposing type of methylation alteration in these cancers, namely, hypermethylation in a tumor-suppressor gene region that is frequently hypermethylated in breast cancers. We found that increased methylation in the E-cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor-suppressor gene regions may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer-promoting chromosomal re-arrangements.
Insights
DNA hypomethylation, particularly in chromosome 1 satellite 2 regions, is linked to chromosomal instability and breast cancer. This demethylation, alongside tumor-suppressor gene hypermethylation, may drive tumorigenesis.
Area of Science:
- Epigenetics
- Cancer Biology
- Human Genetics
Background:
- DNA hypomethylation is associated with karyotypic instability and chromosomal rearrangements, particularly in the pericentromeric regions of chromosome 1.
- These alterations are observed in various cancers, including breast adenocarcinoma, and in rare genetic disorders like ICF syndrome (immunodeficiency, centromeric region instability, facial anomalies).
Purpose of the Study:
- To investigate DNA methylation patterns in breast adenocarcinomas, focusing on satellite 2 DNA in chromosome 1's pericentromeric heterochromatin.
- To examine the correlation between hypomethylation in satellite 2 DNA and hypermethylation in the E-cadherin promoter region in breast cancers.
Main Methods:
- Analysis of DNA methylation status in satellite 2 DNA and the E-cadherin promoter region in breast adenocarcinoma samples and non-malignant breast tissues.
- Comparison of methylation patterns between cancerous and non-cancerous breast tissues.
Main Results:
- Nearly half of the examined breast adenocarcinomas showed hypomethylation in satellite 2 DNA, a region normally highly methylated.
- One non-malignant fibrocystic breast tissue sample also exhibited satellite 2 DNA hypomethylation.
- Increased E-cadherin promoter hypermethylation and satellite 2 DNA hypomethylation frequently co-occurred in the same breast cancer samples.
Conclusions:
- Hypomethylation of satellite 2 DNA in chromosome 1 is a frequent finding in breast adenocarcinomas, suggesting a role in genomic instability.
- The concurrent hypomethylation of satellite 2 DNA and hypermethylation of tumor-suppressor genes like E-cadherin may contribute to breast cancer development.
- Demethylation of specific DNA sequences could predispose to cancer-promoting chromosomal rearrangements.