BERKELEY, CA (UroToday.com) - The Kallikrein (KLK) gene family has been implicated in tumor invasion, metastasis, and angiogenesis and has emerged as an important family of cancer biomarkers, with PSA being the most recognized member. Therefore, understanding the regulatory mechanisms of this family of proteases can provide important information on cancer pathogenesis. Epigenetic biomarkers such as methylated genes are emerging as an exciting area of research that holds promise for potential applications in diverse clinical settings. However, very few studies to date have systematically investigated DNA methylation of KLK genes.
| "Our study now paves the way for future studies of DNA methylation of other KLK genes." |
In this study, we have examined DNA methylation as a potential regulatory mechanism of KLK genes and its contribution to prostate cancer pathogenesis. We have characterized promoter methylation status of KLK6 and KLK10 genes in two independent cohorts of PCa patients operated by radical prostatectomy, between 2007-2011 (cohort I, n = 150) and 1998-2001 (cohort II, n = 124). These KLKs were chosen for analysis based on our earlier genome-wide CpG Island microarray profiling studies of Gleason score 6 versus Gleason score 8 prostate tumors. Our genome-wide array profiling studies identified novel, differentially methylated CpG islands within KLK6 and KLK10 genes in prostate cancer. We used Agilent array platform representing approximately 27,800 CpG Islands. Although this provided a substantially wide-enough genome-wide coverage, not all CpG islands within the KLK locus were represented on these arrays. Our study now paves the way for future studies of DNA methylation of other KLK genes.
Using a high-throughput, quantitative, methylation-specific real-time PCR technique called Methylight, we found significant, tumor specific DNA hypermethylation of KLK6 and KLK10 in prostate cancer compared to matched normal tissue in both cohorts. KLK10 DNA methylation could distinguish cancer from normal tissues with an area under the receiver operating characteristic curve of 82%, implying a diagnostic potential of KLK10 DNA methylation. Further, we found that the KLK6 DNA methylation observed in normal tissue significantly correlated with the methylation in the matched cancerous tissue and thus can be a potential marker of field cancerization in normal peripheral zone prostate tissue.
Our studies have demonstrated a significant association between KLK6 hypermethylation and advanced pathological stage only in cohort I while KLK10 hypermethylation was significantly associated with advanced pathological stage in both cohorts. A major strength of our study is the use of two independent cohorts. This serves to validate the results and show a marked consistency of findings for KLK10 DNA methylation across the 2 cohorts.
We also found that patients with low levels of KLK10 DNA methylation had a significantly shorter time to biochemical recurrence than patients with high levels of KLK10 DNA methylation in cohort II. Due to the recent recruitment period of cohort I, collection of follow-up data is still in progress. Therefore, analysis of association between biochemical recurrence and DNA methylation was not performed in this cohort.
The results suggest that KLK10 DNA methylation may be useful in a pretreatment setting to accurately identify men with prostate cancer who are at risk of developing aggressive disease, perhaps in combination with already existing nomograms.
Written by:
Ekaterina Olkhov-Mitsela and Bharati Bapatb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aSamuel Lunenfeld Research Institute; Mount Sinai Hospital; Toronto, ON Canada; Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto, ON Canada
bSamuel Lunenfeld Research Institute; Mount Sinai Hospital; Toronto, ON Canada; Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto, ON Canada; Department of Pathology; University Health Network; University of Toronto; Toronto, ON Canada
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