Age-related DNA methylation changes in normal human prostate tissues.
OBJECTIVE
Prostate cancer is a leading cause of cancer death among the aging male population but the mechanism underlying this association is unclear. Aberrant methylation of promoter CpG islands is associated with silencing of genes and age-dependent methylation of several genes has been proposed as a risk factor for sporadic cancer. We examined the extent of gene methylation in pathologically normal human prostate as a function of age.


METHODS
We used pyrosequencing to quantitatively analyze the methylation status of nine CpG islands in normal prostate tissue DNA from 45 organ donors and 45 patients who had undergone cystoprostatectomy for bladder cancer. We also analyzed 12 pairs of matched benign and prostate cancer tissue DNA from patients with prostate cancer.


RESULTS
Linear regression analysis revealed a significant increase in promoter methylation levels correlating with age for CpG islands at RARbeta2 (r = 0.4; P < 0.0001), RASSF1A (r = 0.27; P = 0.01), GSTP1 (r = 0.59; P < 0.0001), NKX2-5 (r = 0.27; P = 0.008), and ESR1 (r = 0.244; P = 0.023) in the normal prostate tissue samples studied. A calculated average methylation (z score) at all nine CpG loci analyzed in the normal prostate tissues showed a strong correlation with age (r = 0.6; P < 0.001). Comparison of the methylation level for the matched benign and prostate cancer tissues from individual patients with prostate cancer showed significantly higher methylation in the prostate cancer tissue samples for RARbeta2 (P < 0.001), RASSF1A (P = 0.005), GSTP1 (P < 0.001), NKX2-5 (P = 0.003), ESR1 (P = 0.016), and CLSTN1 (P = 0.01).


CONCLUSIONS
Our findings show aberrant hypermethylation as a function of age in the normal prostate tissues. Such age-related methylation may precede and predispose to full-blown malignancy.
Kwabi-Addo
Bernard
B
Department of Pathology, Baylor College of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. bernardk@bcm.tmc.edu
Chung
Woonbok
W
Shen
Lanlan
L
Ittmann
Michael
M
Wheeler
Thomas
T
Jelinek
Jaroslav
J
Issa
Jean-Pierre J
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics; D012044:Regression Analysis; D017422:Sequence Analysis, DNA
D017931:DNA Primers