Author(s)

Anne H. O’Donnell^1,2, John R. Edwards³, Robert A. Rollins^1,4, Nathan D. Vander Kraats³, Tao Su⁵, Hanina H. Hibshoosh⁵, Timothy H. Bestor^1*

¹Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
²Division of Genetics, Boston Children’s Hospital, Boston, MA, USA.
³Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO, USA.
⁴Pfizer BioTherapeutics Research and Development, Center for Integrative Biology and Biotherapeutics, Pearl River, NY, USA.
⁵Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.

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.

DNA Methylation, Mammary Carcinoma

O’Donnell, A. , Edwards, J. , Rollins, R. , Kraats, N. , Su, T. , Hibshoosh, H. and Bestor, T. (2014) Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis. Journal of Cancer Therapy, 5, 1311-1324. doi: 10.4236/jct.2014.514131.