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

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Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer Human Cancer Biology Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer Yu-Chuen Huang,1Cheng-Ming Lee,1Marcelo Chen,1,4 Ming-Yi Chung,2,5 Yen-Hwa Chang,3,6 William Ji-Shian Huang,3,6 Donald Ming-Tak Ho,7 Chin-Chen Pan,3,7 Tony T. Wu,8 Stone Yang,4 Ming-Wei Lin,1, 5 Jer-Tsong Hsieh,9 and Yi-Ming Arthur Chen1 Abstract 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 GNMTexpression 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 GNMTexpression in normal prostatic and benign prostatic hy- perplasia 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. Prostate cancer is the third most common cancer for men prostate cancer include age, race, and family history of prostate throughout the globe and the most common cancer among men cancer. Secondary risk factors that have been implicated are diet, in North America, Europe, and some parts of Africa (1). Asian androgens, occupational chemicals, smoking, inflammation, populations have much lower incidence rates, especially among and obesity (2). Chinese (2). Well-documented risk factors associated with Changes in DNA methylation are found during the initial and progressive stages of many human tumors. Alterations appear- ing as either hypomethylation or hypermethylation can lead to Authors’ Affiliations: 1Division of Preventive Medicine, Institute of Public Health, chromosomal instability and transcriptional gene silencing (3), 2 3 Faculty of Life Sciences and Institute of Genome Sciences, and School of both of which have been identified in prostate cancer cases (4). Medicine, National Yang-Ming University; 4Department of Urology, Mackay Memorial Hospital; 5Department of Medical Research and Education, 6Division of Results from animal experiments show that diets deficient in Urology, Department of Surgery, and 7Department of Pathology and Laboratory methyl group donors (e.g., choline and methionine) or methyl Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;8Division of Urology, group metabolism coenzymes (e.g., folate and vitamin B12) Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; result in disturbances in intracellular S-adenosylmethionine and 9Department of Urology, University of Texas Southwestern Medical Center, Dallas,Texas levels, trigger DNA hypomethylation, and promote cancers of Received 6/26/06; revised 10/23/06; accepted 12/12/06. the liver, prostate, and other organs (5). Grant support: Veterans General Hospital, Tsou Foundation, and National Yang- Glycine N-methyltransferase (GNMT; EC2.1.1.20), a protein Ming University Joint Research Program grant VTY92-P5-32 and Mackay with multiple functions, affects genetic stability by regulating Memorial Hospital and National Yang-Ming University Joint Research Program the ratio of S-adenosylmethionine to S-adenosylhomocysteine, grants MMHYM93-N010-016 and MMHYM94-016. The costs of publication of this article were defrayed in part by the payment of page binding to folate (6, 7), and interacting with environmental charges. This article must therefore be hereby marked advertisement in accordance carcinogens, such as benzo(a)pyrene (8). Previously, we with 18 U.S.C. Section 1734 solely to indicate this fact. identified GNMT as a tumor susceptibility gene for human Requests for reprints: Yi-Ming Arthur Chen, Institute of Public Health, National hepatocellular carcinoma (HCC; refs. 9, 10). We mapped the Yang-Ming University, Shih-Pai, Taipei 112, Taiwan. Phone: 886-2-28267193; Fax: 886-2-28270576; E-mail: [email protected]. human GNMT gene to the 6p12chromosomal region and F 2007 American Association for Cancer Research. characterized its polymorphism (10, 11). Genotypic analyses of doi:10.1158/1078-0432.CCR-06-1551 several human GNMT gene polymorphisms using a special Clin Cancer Res 2007;13(5) March 1, 2007 1412 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2007 American Association for Cancer Research. GNMT Is aTumor Susceptibility Gene for Prostate Cancer formula, we reported that 36% to 47% of the HCC tissues have Determination of the genetic polymorphisms of GNMT using GeneScan, loss of heterozygosity (LOH) of GNMT gene (11). Because Taqman, and denaturing high-performance liquid chromatography GNMT only expresses in the liver, pancreas, prostate, and assays. Genomic DNA was obtained from the PBMCs using a kidney (10), we hypothesized that GNMT is also a tumor conventional phenol/chloroform extraction method followed by À j susceptibility gene for prostate cancer. ethanol precipitation. All DNA samples were stored at 20 C. As shown in Fig. 1A, three polymorphisms of GNMT, including the short In this report, we designed a case-control study to analyze tandem repeat polymorphism 1 (STRP1), 4-bp insertion/deletion associations between different GNMT haplotypes and prostate polymorphisms (INS/DEL), and single-nucleotide polymorphism 1 cancer. Results from a phenotypic analysis showed that one (SNP1), were analyzed in this study. Automated fragment analysis GNMT haplotype exerting a protective effect against prostate (GeneScan) was used to detect instances of STRP1 and INS/DEL. cancer had the highest level of promoter activity. We also Details of the methods and primers used have been described investigated the GNMT LOH rate in tumorous specimens by previously (11). In brief, PCR was done using a GeneAmp PCR 9700 comparing their genotypes with those found in peripheral thermocycler (Applied Biosystems, Foster City, CA). The sizes of the blood mononuclear cells (PBMC). Finally, immunohistochem- PCR products were elucidated by using an ABI 377 PRISM sequencer ical staining was used to analyze GNMT gene expression level; (Applied Biosystems) with a GeneScan 400 size standard and the results indicate that GNMT was down-regulated in most of Genotyper analytic software (Applied Biosystems). For quality control the prostatic tumor specimens. purposes, DNA samples from Huh 7 and Hep 3B cell lines whose genotypes have been determined previously were included in each set of experiments (11). The SNP1 was determined using a Taqman 5¶-nuclease assay, which Materials and Methods has been described previously (11). In addition, about one third (112) of samples were randomly selected for denaturing high-performance Participants and specimens. Between 2000 and 2005, 326 prostate liquid chromatography assay (16). Denaturing high-performance cancer patients were recruited from postsurgery follow-up clinics at three liquid chromatography was carried out using an automated high- Taiwanese hospitals: Taipei Veterans General Hospital (Taipei, Taiwan), performance liquid chromatography instrument equipped with a DNA Taipei Mackay Memorial Hospital (Taipei, Taiwan), and Kaohsiung separation column (Transgenomic, San Jose, CA). PCR was done in a Veterans General Hospital (Kaohsiung, Taiwan). Pathologic examina- 25 AL reaction volume containing 25 ng of genomic DNA, 0.3 Amol/L tions of specimens obtained from transrectal ultrasound-guided biopsy of each primer, 200 Amol/L deoxynucleotide triphosphates, 2.5 ALof  have been done on all the patients and the diagnosis was confirmed. The 10 PCR buffer containing MgCl2 (Applied Biosystems), and 0.625 demographic and clinical data, including disease stage, Gleason scores, unit of AmpliTaq Gold polymerase (Applied Biosystems). The primers and prostate-specific antigen (PSA) levels, were collected through used for denaturing high-performance liquid chromatography were reviewing medical records of the patients. The disease stages of the identical to those used in the Taqman assay. The PCR consisted of 35 patients were determined using the definition proposed by the American cycles at 95jC for 30 s, 64jC for 30 s, and 72jC for 30 s in a GeneAmp Joint Committee on Cancer tumor-nodes-metastasis system (2002). All PCR 9700 thermocycler followed by denaturation at 95jC for 10 min the patients were Chinese descendants
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