Global DNA hypomethylation in prostate cancer development and progression: a systematic review.
BACKGROUND
The role of global DNA methylation in prostate cancer (PCa) remains largely unknown. Our aim was to summarize evidence on the role of global DNA hypomethylation in PCa development and progression.


METHODS
We searched PubMed through December 2013 for all studies containing information on global methylation levels in PCa tissue and at least one non-tumor comparison tissue and/or studies reporting association between global methylation levels in PCa tissue and survival, disease recurrence or at least one clinicopathological prognostic factor. We summarized results using non-parametric comparisons and P-value summary methods.


RESULTS
We included 15 studies in the review: 6 studies with both diagnostic and prognostic information, 5 studies with only diagnostic information and 4 studies with only prognostic information. Quantitative meta-analysis was not possible because of the large heterogeneity in molecular techniques, types of tissues analyzed, aims and study designs. Summary statistical tests showed association of DNA hypomethylation with PCa diagnosis (P<0.006) and prognosis (P<0.001). Restriction to studies assessing 5-methylcytosine or long interspersed nucleotide element-1 revealed results in the same direction. Analyses restricted to specific clinicopathological features showed association with the presence of metastasis and tumor stage in all tests with P<0.03, and no association with Gleason score (all tests P>0.1 except for the weighted Z-test, P=0.05).


CONCLUSIONS
DNA hypomethylation was associated with PCa development and progression. However, due to the heterogeneity and small sample sizes of the included studies, along with the possibility of publication bias, this association requires additional assessment.
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
R
R
Zelic
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
V
V
Fiano
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
C
C
Grasso
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
D
D
Zugna
Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
A
A
Pettersson
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
A
A
Gillio-Tos
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
F
F
Merletti
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, and CPO-Piemonte, Turin, Italy.
L
L
Richiardi
D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D039781:PubMed