It has long been believed that abnormal DNA methylation turns of tumor suppressor genes during carcinogenesis, but no biomarker or therapeutic approach has resulted. We find that abnormal de novo methylation at tumor suppressor genes is very rare, and that the dominant abnormality is a loss of DNA methylation across the genome. While demethylation in cancer has been regarded as a contributor to tumor progression, the data shown here indicate instead that is more likely to be a manifestation of a methylation-based antitumor system that induces apoptosis of tumor cells and elicits an antitumor immune response. Further investigation of genome demethylation in cancer may produce new approaches to diagnosis and treatment. Demethylation occurs early in tumorigenesis, and it may be possible to devise treatments that will augment the methylation suicide pathway so as to reduce the incidence or severity of malignant disease. The stability and sensitivity of detection of DNA biomarkers as compared to other biomolecules suggests that the identification of DNA methylation biomarkers through whole-genome methylation profiling could be effective in enhancing early diagnosis.

Public Health Relevance

Our preliminary data and re-examination of published data have led us to re-evaluate the role of abnormalities of genomic methylation patterns in breast cancer. We conclude that the methylation abnormalities that occur curing carcinogenesis are likely to be a manifestation of a protective system that kills incipient cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA170546-02
Application #
8520272
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Program Officer
Okano, Paul
Project Start
2012-08-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$312,080
Indirect Cost
$117,030
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Terry, Kathryn L; Karageorgi, Stalo; Shvetsov, Yurii B et al. (2013) Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prev Res (Phila) 6:811-21