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Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer

Authors' Affiliations: ¹ Division of Preventive Medicine, Institute of Public Health, ² Faculty of Life Sciences and Institute of Genome Sciences, and ³ School of Medicine, National Yang-Ming University; ⁴ Department of Urology, Mackay Memorial Hospital; ⁵ Department of Medical Research and Education, ⁶ Division of Urology, Department of Surgery, and ⁷ Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; ⁸ Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; and ⁹ Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Yi-Ming Arthur Chen, Institute of Public Health, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan. Phone: 886-2-28267193; Fax: 886-2-28270576; E-mail: arthur{at}ym.edu.tw.

Purpose: 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.

Experimental Design: 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.