Smoking influences aberrant CpG hypermethylation of multiple genes in human prostate carcinoma.
BACKGROUND
Aberrant CpG methylation profiles of gene promoters and their correlation with advanced pathologic features have been well investigated in prostate carcinoma (PC). Several case-control and prospective studies have revealed a positive association between current smoking and PC. The authors hypothesized that smoking influences both progression and prognosis of PC through CpG hypermethylation of related genes.


METHODS
A total of 164 PC patients (52 current, 30 former, and 82 never smokers) and 69 benign prostatic hyperplasia (BPH) patients were examined by methylation-specific PCR (MSP) for 3 genes: adenomatous polyposis coli (APC), glutathione S-transferase pi (GSTP1), and multidrug resistance one (MDR1). The methylation status of representative samples was confirmed by bisulfite DNA sequencing analysis. The newly defined methylation score (M-score) of each sample is the sum of the corresponding log hazard ratio (HR) coefficients derived from multivariate logistic regression analysis for pathology (BPH vs. PC), and was related to clinical and pathologic outcome including smoking status.


RESULTS
The M-score was significantly higher in the current smokers than in never smokers (P = 0.008). Spearman rank correlation test demonstrated a significant correlation between pack-years smoked and M-score in PCs (P = 0.039). Significant correlation of the M-score methylation was observed with high pT category (P < 0.001), high Gleason sum (P < 0.001), high preoperative prostate-specific antigen (PSA) (P = 0.041), and advanced pathologic features. In addition, Gleason sum was significantly associated with PSA failure-free probability as a poor outcome (P = 0.020).


CONCLUSIONS
This is the first study to demonstrate significant correlation of the methylation status of multigenes with smoking status in PC. Smoking status may influence both progression and prognosis of PC through CpG hypermethylation of related genes.
Enokida
Hideki
H
Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.
Shiina
Hiroaki
H
Urakami
Shinji
S
Terashima
Masaharu
M
Ogishima
Tatsuya
T
Li
Long-Cheng
LC
Kawahara
Motoshi
M
Nakagawa
Masayuki
M
Kane
Christopher J
CJ
Carroll
Peter R
PR
Igawa
Mikio
M
Dahiya
Rajvir
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D012044:Regression Analysis; D012907:Smoking / Q000009:adverse effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D025601:Adenomatous Polyposis Coli Protein; D051549:Glutathione S-Transferase pi