Global Methylation Profiling for Risk Prediction of Prostate Cancer

Global Methylation Profiling for Risk Prediction of Prostate Cancer

1. Saswati Mahapatra1,
2. Eric W. Klee3,
3. Charles Y.F. Young1,
4. Zhifu Sun3,
5. Rafael E. Jimenez2,
6. George G. Klee2,
7. Donald J. Tindall1, and
8. Krishna Vanaja Donkena1

+ Author Affiliations

1. Authors' Affiliations: Departments of ¹Urology and ²Laboratory Medicine and Pathology, ³Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota

1. Corresponding Author:
   Krishna Vanaja Donkena, Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Guggenheim 5-01B, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-4226; Fax: 507-284-3757; E-mail: donkena.krishna@mayo.edu

Abstract

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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. Clin Cancer Res; 18(10); 2882–95. ©2012 AACR.

This article is featured in Highlights of This Issue, p. 2721

Footnotes

• Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

• Received August 12, 2011.
• Revision received February 3, 2012.
• Accepted March 2, 2012.

• ©2012 American Association for Cancer Research.