Epigenetic Variations in Prostate Tumors May Determine Choice Between Definitive Treatment and Active Surveillance

Julio M. Pow-Sang, MD

Chair of Genitourinary Oncology

Moffitt Cancer Center,

Tampa, FL

Prostate cancer is the most common cancer and second leading cause of cancer mortality in American men. Nevertheless, it is estimated that only 3% of the patients will die because of their cancer, while the majority will die of competing causes. The main challenge for the physician advising men with prostate cancer is distinguishing the majority of nonlethal cancers from the fewer aggressive ones that will directly impact quality of life and survival.

Active surveillance is proposed as a management option for men with early, localized prostate cancer. This management strategy consists of following men after diagnosis with periodic prostate-specific antigen levels and prostate biopsies. Intervention with definitive treatment (surgery or radiation therapy) is considered only if the cancer develops aggressive characteristics.

In an effort to distinguish aggressive from indolent prostate cancer cases, Jong Y. Park, PhD, investigated genetic and epigenetic variations as biomarkers that may better predict prognosis. Numerous studies support the role of genetic factors in the development and progression of prostate cancer.¹ Recent emerging molecular biological technologies taught us that epigenetic alterations such as DNA methylation within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer.² Promoter hypermethylation of critical genes could become potential biomarkers and therapeutic targets for prostate cancer. Therefore, we investigated genetic and epigenetic variations among patients who were treated at Moffitt Cancer Center.

Park and his team are currently working on genetic polymorphisms and differentially methylated genes associated with the progression of prostate cancer. More than 70 genetic changes and 40 methylated genes have been identified for progression of prostate cancer.³ These genes are involved in critical pathways, such as angiogenesis, DNA repair, and invasion/metastasis. These findings may provide new information of the pathogenesis, the potential to predict the behavior and to provide personalized treatment of prostate cancer. Some epigenetic alterations in prostate tumors currently are being translated into clinical practice for therapeutic use.

Role of DNA Methylation in Cancer: Unmethylated and methylated CpG sites are indicated by white and black circles, respectively. This figure shows a representative region of genomic DNA in normal and tumor cells. The promoter regions in Gene 1, Gene 2, and the tumor suppressor gene (TSG) are rarely methylated in normal cells and, therefore, expressed. CpG islands in the promoter region of the tumor suppressor gene are methylated, and it results in gene silencing. Conversely, hypomethylation in the promoter region of the oncogene in the tumor reactivates transcription.

In clinical practice, active surveillance has been offered at Moffitt for more than a decade, and our clinical team recently reported on the long-term outcomes of men pursuing this management option. The study confirms the findings from previous reports concluding that the cancer-specific survival at a greater than 10-year follow-up in men electing this management strategy was close to 100%.⁴ We also recently reported on the challenges of selecting and following men who elect active surveillance and presented a management algorithm for better selection and follow-up.⁵

Our imaging team, led by Eric Outwater, MD, and Donald Klippenstein, MD, is investigating the application of imaging technology to better define tumors within the prostate and potentially assist in defining the biological potential of a specific tumor. To this end, Outwater is evaluating multiparametric MRI and Klippenstein ultrasound elastography.

The role of focal therapy is controversial at present, and many centers are exploring the use of ablative technologies. At our institution, we evaluated the use of bipolar radio-frequency ablation and determined that the procedure is feasible and safe.⁶

Prostate cancer research at the basic and clinical level is progressing rapidly. Better characterization of tumors will lead to more personalized treatment approaches. Newer technologies offer the potential of controlling cancer while minimizing side effects with consequent improvements in patients’ quality of life.

References

1. Eeles RA, Kote-Jarai Z, Al Olama AA, et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet. 2009;41(10):1116-1121.
2. Yang M, Park JY. DNA methylation in promoter region as biomarkers in prostate cancer. Methods Mol Biol. 2012;863:67-109.
3. Lin HY, Amankwah EK, Tseng TS, et al. SNP-SNP interaction network in angiogenesis genes associated with prostate cancer aggressiveness. PLoS One. 2013;8(4):e59688.
4. Buethe DD, Russell C, Yue B, et al. Long-term outcomes of active surveillance of prostate cancer: 10 years later. J Clin Oncol. 2013;31(suppl 6; abstr 170).
5. Buethe DD, Pow-Sang J. Enrollment criteria controversies for active surveillance and triggers for conversion to treatment in prostate cancer. J Natl Compr Canc Netw. 2012;10(9):1101-1110.
6. Pow-Sang JM, Biagioli M, Outwater E, et al. Focal radio-frequency ablation for low-risk, focal prostate cancer: challenges and technique. Presented at: 5th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer; June 6-8, 2012; Durham, NC. Poster P-31.