DNA methylation in benign breast epithelium in relation to age and breast cancer risk.
BACKGROUND
Many established breast cancer risk factors are related to the timing and duration of exposure to reproductive hormones, which are known to drive breast epithelial cell proliferation. The epigenetic molecular clock hypothesis suggests that CpG island methylation records the cell division history of benign epithelium. In proliferative epithelium, such as breast, this may provide an individualized cell-based measure of cancer risk.


METHODS
Methylation of cyclin D2, APC, HIN1, RASSF1A, and RAR-beta2 was measured by quantitative multiplex methylation-specific PCR in 290 benign and malignant breast epithelial cell samples obtained by palpation-directed fine-needle aspiration biopsy from 164 women. Univariate, multivariate, and unsupervised cluster analysis was used to establish the relationship between TSG methylation and a personal history of breast cancer, predicted breast cancer risk, and specific breast cancer risk factors.


RESULTS
RASSF1A methylation was highly correlated with breast cancer risk [odds ratio (OR), 5.28; 95% confidence interval (95% CI), 1.95-14.32; P = 0.001], atypical cytology (OR, 4.11; 95% CI, 1.30-12.98; P = 0.016), and benign breast disease requiring biopsy (OR, 6.12; 95% CI, 1.41-26.51; P = 0.016). RASSF1A methylation increased linearly between ages 32 and 55. Increasing parity was associated with decreased APC methylation.


CONCLUSIONS
TSG methylation increases in benign breast epithelium with increasing age. Because it is independently related to a personal history of benign or malignant breast disease and to predicted breast cancer risk, it may have value for breast cancer risk stratification and as a surrogate endpoint marker in prevention trials.
Euhus
David M
DM
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA. david.euhus@utsouthwestern.edu
Bu
Dawei
D
Milchgrub
Sara
S
Xie
Xian-Jin
XJ
Bian
Aihua
A
Leitch
A Marilyn
AM
Lewis
Cheryl M
CM
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D044963:Biopsy, Fine-Needle; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D018899:CpG Islands / Q000235:genetics; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D004848:Epithelium / Q000473:pathology; D005260:Female; D017491:Genes, APC; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D016207:Cytokines; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta