Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk.
BACKGROUND
The tumor suppressor genes RASSF1A, APC, H-cadherin, RARbeta2, and cyclin D2 are methylated more frequently in breast cancer than in adjacent benign tissue. However, it is unclear whether promoter methylation of tumor suppressor genes in benign breast tissue is associated with an increased risk for breast cancer.


METHODS
Promoter hypermethylation was measured in benign and malignant breast samples obtained by fine needle aspiration biopsy from 27 breast cancer patients and 55 unaffected women whose risk of breast cancer had been defined using the Gail, Claus, and BRCAPRO models.


RESULTS
Cyclin D2 methylation occurred in 57% of tumor samples but not in corresponding benign breast samples and in only one sample from an unaffected patient (P < 0.0001). RARbeta2 methylation occurred in 32% of benign breast samples from cancer patients but only 9% of similar samples from unaffected women (P = 0.002). Promoter methylation of RASSF1A and APC occurred more frequently (70% and 56%, respectively) in unaffected women at high-risk for breast cancer as defined by the Gail model than in low/intermediate risk women (29% and 20%, P = 0.04 and P = 0.03). Of the Gail model risk factors, only number of prior breast biopsies was highly correlated with APC and RASSF1A methylation (P = 0.0001 and 0.02, respectively).


CONCLUSIONS
Since cyclin D2 promoter methylation occurs almost exclusively in tumors, it may be possible to exploit it for the early detection of breast cancer. Promoter methylation of APC, RARbeta2, and RASSF1A in benign breast epithelium is associated with epidemiologic markers of increased breast cancer risk.
Lewis
Cheryl M
CM
Hamon Center for Therapeutic Oncology Research, Department of Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9155, USA.
Cler
Leslie R
LR
Bu
Da-Wei
DW
Zöchbauer-Müller
Sabine
S
Milchgrub
Sara
S
Naftalis
Elizabeth Z
EZ
Leitch
A Marilyn
AM
Minna
John D
JD
Euhus
David M
DM
D000328:Adult; D000367:Age Factors; D000368:Aged; D001706:Biopsy; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008875:Middle Aged; D008962:Models, Theoretical; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011486:Protein C / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
C080336:CCND2 protein, human; D015820:Cadherins; D056742:Cyclin D2; D016213:Cyclins; C099972:H-cadherin; D011486:Protein C; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta