Methylation of multiple genes in prostate cancer and the relationship with clinicopathological features of disease.
Promoter methylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. We examined the methylation status of glutathione s-transferase Pi1 (GSTP1), retinoic acid receptor beta (RARB), CD44, E-cadherin (ECAD), RAS association domain family protein 1A (RASSF1A) and endothelin B receptor (EDNRB) genes in 81 prostate cancer and 42 benign prostatic hyperpasia specimens. Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. Methylation-specific PCR (MSP) was carried out after bisulfite treatment of genomic DNA. Methylation frequencies in prostate cancer and benign prostatic hyperplasia were 72% and 5% for GSTP1, 40% and 0% for RARB, 72% and 38% for CD44, 61% and 14% for ECAD, 49% and 19% for RASSF1A and 72% and 62% for EDNRB, respectively. Methylation of GSTP1, RARB, CD44, ECAD and RASSF1A, but not of EDNRB was detected at a statistically higher frequency in prostate cancer than in the benign prostatic hypertrophy specimens. Methylation of RARB occurred more frequently in early onset (age <55 years) as compared to late onset disease (age >70 years) (odds ratio, 8.6; 95% CI, 1.4-51.4; P=0.02). Methylation of RARB also occurred more frequently in stage III as compared to stage II disease (odds ratio, 3.2; 95% CI, 1.1-8.8; P=0.03). A methylation index (MI) was calculated as the total number of genes methylated, excluding EDNRB. A trend toward higher MI was noted in stage III as compared to stage II disease, and in Gleason score 7 as compared to Gleason score 6 tumors. Our results suggest that the methylation of selected genes in prostate cancers correlates with clinicopathological features of poor prognosis.
Division of Hematology and Oncology, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue (D8-4), Suite 3300, Miami, FL 33136, USA. rsingal@med.miami.edu
Rakesh
R
Singal
Larry
L
Ferdinand
Isildinha M
IM
Reis
James J
JJ
Schlesselman
D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044023:Receptor, Endothelin B / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015820:Cadherins; D018960:Hyaluronan Receptors; D007527:Isoenzymes; C411762:RASSF1 protein, human; D044023:Receptor, Endothelin B; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D004247:DNA; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase