Patterns of DNA Methylation May Differentiate Indolent and Aggressive Prostate Cancers

Angela H. Ting, PhD

Key Points

• There is a critical need to characterize molecular differences between indolent and aggressive prostate cancer.
• Epigenetic alterations such as DNA methylation are important in carcinogenesis and can capture tumors’ regulatory state.
• A genome-wide analysis of differential methylation patterns among benign prostatic tissue and low- and high-grade tumors found extensive focal hypermethylation regions unique to high-grade disease.
• These methylation changes provide crucial molecular distinctions between indolent and aggressive prostate cancer and may serve as the basis for potential diagnostic tests.

Prostate cancer continues to be a serious healthcare problem with approximately 220,800 new cases reported in the United States in 2015. The disease course of prostate cancer is heterogeneous and ranges from slow-growing, indolent forms to aggressive, potentially life-threatening forms. Unfortunately, distinguishing between indolent and more aggressive prostate cancers is difficult with currently available markers.

The findings of a study conducted at the Lerner Research Institute of the Cleveland Clinic in collaboration with Eric A. Klein, MD, Chairman of the Glickman Urological and Kidney Institute and Cristina Magi-Galluzzi, MD, PhD, Director of Genitourinary Pathology in the Department of Anatomic Pathology were recently published in the journal Cell Reports. This study used advanced molecular techniques to characterize differences between indolent and more aggressive forms of prostate cancer. According to Angela H. Ting, PhD from the Genomic Medicine Institute at the Lerner Research Institute, this study of DNA methylation patterns not only advances our understanding of the development of prostate cancer, but may eventually lead to diagnostic tools to identify patients with the most aggressive forms of cancer.

DNA methylation is an epigenetic alteration that plays a role in prostate cancer

Both genetic mutations and epigenetic alterations (i.e., chemical changes to tumor DNA, such as DNA methylation) are believed to be important in carcinogenesis. Dr. Ting explains that DNA methylation is a process that controls whether a gene is expressed, meaning whether the gene is turned off or on. She further indicates that “DNA methylation was selected for study based on the observed low mutation rate in prostate cancers relative to other cancers. The low mutation rate suggests that mechanisms other than genetic mutations are involved, which motivated us to investigate the role of epigenetic changes in the biology of prostate cancers.”

The intriguing results show differences in DNA methylation patterns

Dr. Ting and her coworkers choose to stratify the prostate tumors studied by histology classified by Gleason scores. The samples were divided into three groups: benign prostatic tissue, low grade (indolent, Gleason score 6) prostate cancer, and high grade (aggressive, Gleason score 8 to 10) prostate cancer. “By stratifying prostate cancer samples using Gleason score derived from radical prostatectomy, our results relate to biological criteria, as opposed to stratifications using recurrence that are influenced by stage of disease at presentation” says Dr. Ting.

Figure 1. The comparison of benign, low-grade, and high-grade prostate tumors showed that high-grade tumors had pervasive focal hypermethylation. Hypermethylated DNA is indicated by black circles and unmethylated DNA is represented by white circles. High-grade DMRs occurred more frequently at intergenic regions and gene bodies than other genomic contexts. In addition, the intergenic DMRs appear highly enriched for DNaseI hypersensitivity sites, which are markers for regulatory DNA regions. Genes near the DMRs regulate cellular activities, such as cellular motility that are purported to play a role in aggressive disease.