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Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis
Anne H O'Donnell1, John R Edwards2, Robert A Rollins3
1Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, NY, USA ; Division of Genetics, Boston Children's Hospital, Boston, MA, USA.
Abstract:
Promoter silencing by ectopic de novo methylation of tumor suppressor genes has been proposed as comparable or equivalent to inactivating mutations as a factor in carcinogenesis. However, this hypotheses had not previously been tested by high resolution, high-coverage whole-genome methylation profiling in primary carcinomas. We have determined the genomic methylation status of a series of primary mammary carcinomas and matched control tissues by examination of more than 2.7 billion CpG dinucleotides. Most of the tumors showed variable losses of DNA methylation from all sequence compartments, but increases in promoter methylation were infrequent, very small in extent, and were observed largely at CpG-poor promoters. De novo methylation at the promoters of proto-oncogenes and tumor suppressor genes occurred at approximately the same frequency. The findings indicate that tumor suppressor silencing by de novo methylation is much less common than currently believed. We put forward a hypothesis under which the demethylation commonly observed in carcinomas is a manifestation of a defensive system that kills incipient cancer cells.
Insights
Promoter silencing via DNA methylation is less common in breast cancer than thought. Widespread DNA demethylation in tumors may be a defense mechanism against cancer cell growth.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Promoter silencing by DNA methylation is a proposed mechanism in carcinogenesis.
- Previous studies lacked high-resolution, whole-genome methylation data in primary carcinomas.
Purpose of the Study:
- To investigate the role of DNA methylation in primary breast carcinomas using high-coverage whole-genome profiling.
- To test the hypothesis that promoter silencing of tumor suppressor genes by de novo methylation is a significant factor in carcinogenesis.
Main Methods:
- Whole-genome methylation profiling of primary mammary carcinomas and matched control tissues.
- Analysis of over 2.7 billion CpG dinucleotides to determine genomic methylation status.
Main Results:
- Most tumors exhibited variable DNA methylation losses across genomic compartments.
- Increases in promoter methylation were infrequent, minimal, and primarily at CpG-poor promoters.
- De novo methylation occurred at similar frequencies at proto-oncogene and tumor suppressor gene promoters.
Conclusions:
- Tumor suppressor gene silencing by de novo methylation is less prevalent in breast cancer than previously assumed.
- Widespread DNA demethylation observed in carcinomas may represent a cellular defense mechanism against incipient cancer cells.
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