Metastatic Prostate Cancer

Very few studies have described CGI hypermethylation patterns in metastatic prostate cancers, due to the difficulty in obtaining metastatic cancer tissue. Surgical resection of metastatic deposits of prostate cancer does not enhance survival from the disease significantly. Therefore, most patients with refractory, metastatic prostate cancer are not candidates for further surgical intervention. Therefore, the few studies that have examined

CGI hypermethylation patterns in metastases obtained these specimens from autopsy cases of patients who died from refractory prostate cancer or from the small group of patients undergoing surgical resection of bone metastases to alleviate symptoms or monitor for response to novel therapies. Over a 7 year period, we systematically collected metastatic prostate cancer specimens at autopsy from 28 men who died of refractory prostate cancer. One to six anatomically distinct metastases from a wide array of sites, including bone, lymph node, liver, adrenal gland, intracranial subdural, and intraprostatic, were obtained from each patient (59).

Using this collection of tissues, we recently demonstrated that the pattern of CGI hypermethylation in prostate cancer metastases is extremely similar to the pattern seen in primary prostate cancer (59) (Figure 4). That is, CGIs at genes such as GSTP1, RASSFla, APC, COX2, and MDR1 remain hypermethylated in the DNA from metastatic prostate cancer deposits at high frequencies, while very few new genes are hypermethylated (59). This would suggest that these methylation patterns are maintained even through the process of metastatic invasion and occupation of distant sites. Indeed, the pattern of CGI hypermethylation is largely maintained in a clonal manner and appears homogeneous across all sites from any given patient (59) (Figure 4). For instance, case 22 exhibits a significant degree of hypermethylation at the hMLHl CGI in his intraprostatic lesion, and this hypermethylation is observed at every one of the other three metastatic deposits. This observation is particularly noteworthy considering hMLHl hypermethylation is very infrequent in prostate cancer (59) (Figure 4). Similarly, in case 32, the MDR1 CGI is not hypermethylated in the intraprostatic lesion and does not become hypermethylated at the other four metastatic deposits. Considering MDR1 CGI sequences are methylated in greater than 85% of primary prostate cancers, it is especially telling that MDR1 CGIs were not hypermethylated in any of the five metastastatic prostate cancer specimens taken from this patient (59) (Figure 4). Additionally, a significant degree of heterogeneity in the CGI hypermethylation pattern is observed when metastatic specimens are grouped by category (lymph node, bone, liver, etc.) of anatomical site involvement. These observations suggest that the CGI hypermethylation pattern does not appear to be affected by the site of metastasis (Figure 4). We tested this hypothesis quantitatively by using a novel biostatistical method called analysis of molecular variance (AMOVA) (59) to assess whether the heterogeneity of the hypermethylation pattern within sites was greater than the heterogeneity of the hypermethylation pattern in the entire collection of metastases. We found that there was a 5-fold greater variability in the hypermethylation profile within each site category than there was across all specimens (p < 0.0001), providing strong statistical evidence that the hypermethylation pattern is not site-specific (59) (Figure 4).


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