Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk.
Inactivation of tumor suppressor genes by promoter methylation is an important mechanism of tumorigenesis. Increased expression of DNA methyltransferases has been commonly observed in cancer. A C/T polymorphism in the DNA methyltransferase 3b (DNMT3b) promoter region results in increased activity and has recently been identified as a risk factor for lung cancer. In this study, we examined the C/T polymorphism of the DNMT3b gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. DNMT3b genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The DNMT3b polymorphism frequencies in the prostate cancer and BPH specimens were, respectively, 20 and 26% for CC, 42 and 52% for CT, and 38 and 21% for TT. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the TT genotype may be associated with an increased risk of prostate cancer: the age-adjusted odds ratio (aOR) was 2.6 [95% confidence interval: 0.8-8.0]; the increase in odds ratio was seen in both blacks and whites (aOR=4.3 in blacks, and 2.0 in whites). The samples used in this study have previously been examined for methylation index (MI) based on the number of genes methylated, the range being 0 to 5. A trend toward an increase in MI was detected for the DNMT3b polymorphisms in prostate cancer patients but not for BPH subjects (mean MI 2.6, 2.9, 3.1 for CC, CT, and TT genotype in prostate cancer; 0.8, 0.8, 0.7 for CC, CT, and TT genotype in BPH subjects). These findings suggest that the DNMT3b polymorphisms may be associated with an increase in promoter methylation of tumor-suppressor genes related to the development of prostate cancer, and may thereby increase the risk of this disease.
Singal
Rakesh
R
Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue (D8-4), Suite 3300, Miami, FL 33136, USA. rsingal@med.miami.edu
Das
Partha M
PM
Manoharan
Murugesan
M
Reis
Isildinha M
IM
Schlesselman
James J
JJ
D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011470:Prostatic Hyperplasia / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics / Q000473:pathology*; D044023:Receptor, Endothelin B / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044465:White People / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D015820:Cadherins; D004248:DNA (Cytosine-5-)-Methyltransferases; D004273:DNA, Neoplasm; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D044023:Receptor, Endothelin B; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; D000097584:DNA Methyltransferase 3B; C411762:RASSF1 protein, human; C082925:retinoic acid receptor beta; C496556:GSTP1 protein, human