Global Methylation Profiling for Risk Prediction of Prostate Cancer

• Published in: Clinical cancer research Vol. 18; no. 10; pp. 2882 - 2895
• Main Authors: MAHAPATRA, Saswati, KLEE, Eric W, YOUNG, Charles Y. F, ZHIFU SUN, JIMENEZ, Rafael E, KLEE, George G, TINDALL, Donald J, VANAJA DONKENA, Krishna
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-05-2012
• Subjects: Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; DNA Methylation; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Middle Aged; Neoplasm Recurrence, Local - diagnosis; Neoplasm Recurrence, Local - genetics; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prognosis; Promoter Regions, Genetic; Prostatic Neoplasms - diagnosis; Prostatic Neoplasms - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Risk factor; Prediction; Malignant tumor; Predictive factor; Methylation; Male genital diseases; Prostate cancer; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-2090

The aim of this study was to investigate the promoter hypermethylation as diagnostic markers to detect malignant prostate cells and as prognostic markers to predict the clinical recurrence of prostate cancer.
DNA was isolated from prostate cancer and normal adjacent tissues. After bisulfite conversion, methylation of 14,495 genes was evaluated using the Methylation27 microarrays in 238 prostate tissues. We analyzed methylation profiles in four different groups: (i) tumor (n = 198) versus matched normal tissues (n = 40), (ii) recurrence (n = 123) versus nonrecurrence (n = 75), (iii) clinical recurrence (n = 80) versus biochemical recurrence (n = 43), and (iv) systemic recurrence (n = 36) versus local recurrence (n = 44). Group 1, 2, 3, and 4 genes signifying biomarkers for diagnosis, prediction of recurrence, clinical recurrence, and systemic progression were determined. Univariate and multivariate analyses were conducted to predict risk of recurrence. We validated the methylation of genes in 20 independent tissues representing each group by pyrosequencing.
Microarray analysis revealed significant methylation of genes in four different groups of prostate cancer tissues. The sensitivity and specificity of methylation for 25 genes from 1, 2, and 4 groups and 7 from group 3 were shown. Validation of genes by pyrosequencing from group 1 (GSTP1, HIF3A, HAAO, and RARβ), group 2 (CRIP1, FLNC, RASGRF2, RUNX3, and HS3ST2), group 3 (PHLDA3, RASGRF2, and TNFRSF10D), and group 4 (BCL11B, POU3F3, and RASGRF2) confirmed the microarray results.
Our study provides a global assessment of DNA methylation in prostate cancer and identifies the significance of genes as diagnostic and progression biomarkers of prostate cancer.