TITLE:
Methylation Abnormalities in Mammary Carcinoma: The Methylation Suicide Hypothesis
AUTHORS:
Anne H. O’Donnell, John R. Edwards, Robert A. Rollins, Nathan D. Vander Kraats, Tao Su, Hanina H. Hibshoosh, Timothy H. Bestor
KEYWORDS:
DNA Methylation, Mammary Carcinoma
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.14,
December
3,
2014
ABSTRACT: Promoter silencing by
ectopicde novomethylation 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 methylationfrom
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 promotersof proto-oncogenes and tumor
suppressor genes occurred at approximately the same frequency. The findings
indicate that tumor suppressor silencing byde
novomethylation 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.