Haplotypes, loss of heterozygosity, and expression levels of glycine N-methyltransferase in prostate cancer.
OBJECTIVE
Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer.


METHODS
Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients.


RESULTS
Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues.


CONCLUSIONS
Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.
Huang
Yu-Chuen
YC
Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Taipei, Taiwan.
Lee
Cheng-Ming
CM
Chen
Marcelo
M
Chung
Ming-Yi
MY
Chang
Yen-Hwa
YH
Huang
William Ji-Shian
WJ
Ho
Donald Ming-Tak
DM
Pan
Chin-Chen
CC
Wu
Tony T
TT
Yang
Stone
S
Lin
Ming-Wei
MW
Hsieh
Jer-Tsong
JT
Chen
Yi-Ming Arthur
YM
D000368:Aged; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D050938:Glycine N-Methyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*
C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase