Grayscale representing % of input alleles that are hypermethylated

Figure 4. Hypermethylation of CpG islands in metastatic prostate cancer. Panel A. There is a relatively high degree of variability in the quantitative CpG island hypermethylation pattern in any given site of metastatic deposit. Panel B. Conversely, the CpG island hypermethylation pattern is highly homogeneous across all sites of metastatic deposit within any given patient. The variability in the quantitative CpG island hypermethylation pattern was 5-fold higher (p < 0.0001) when metastases were grouped by site of anatomical involvement than when all metastases were pooled by patient and sites. This suggests that there is no site-specificity in the CpG island hypermethylation pattern.

Despite the striking similarities between the CGI hypermethylation patterns between the primary and metastatic prostate cancers, there are a few important differences. First, it appears that, on average, the normalized quantity of hypermethylated CGIs at each gene in the metastatic tissues is greater than in the primary cancers (59). However, this difference may simply be due to an artifact resulting from the increased purity of tumor cells in the metastatic tissues compared to the primary prostate cancer tissues.

Second, CGIs at a few genes that are rarely hypermethylated in the primary cancers have been observed to be hypermethylated in a small percentage of metastatic prostate cancer specimens. For instance, the hMLHl CGI was hypermethylated in all four metastatic deposits, including the intraprostatic cancer, from one out of 28 autopsy subjects, while it was never found to be hypermethylated in the primary prostate cancer specimens (59). hMLHl encodes the MutL homolog 1 mismatch repair protein, which is frequently inactivated by mutations and CGI hypermethylation in a wide variety of human cancers (73, 87, 88). Loss of this protein by hypermethylation may occur very late in a small percentage of primary and metastatic prostate cancers, leading to increased genomic instability and further cancer progression.

Additionally, it has been shown that there is a modest, but significant increase in the frequency and quantity of CGI hypermethylation of the ERa gene, which encodes the alpha isoform of the estrogen receptor, in metastatic prostate cancers as compared to primary prostate cancers (59). In the meanwhile, Zhu et al. demonstrated that the opposite trend occurs for the ERfi gene, which codes for the beta isoform of the estrogen receptor (67). While they are hypermethylated in many high Gleason grade prostate cancers, CGIs at ERfi appear to lose their hypermethylation in metastatic prostate cancer tissues from lymph node and bone (67). Although estrogens have been widely used historically for the treatment of advanced prostate cancer, the mechanisms by which they act are still unclear. Though both ERa and ERp bind estrogens, their roles in the regulation of downstream gene expression may be quite divergent (89). While both ERa and ERp are expressed in the normal prostate, their roles in the prostate are largely unknown. However, it has been suggested that ERp may be more important as a negative regulator of prostate growth and proliferation as supported by the observations that: i) mice carrying targeted disruptions in ERfi develop prostatic hyperplasia (90), and ii) though ERp expression is common in normal prostate epithelia, ERp expression is lost in approximately 75% of high grade (Gleason pattern 4 or 5) primary prostate cancers (91). However, this view is complicated by the finding that CGIs at ERfi lose their methylation and the gene is re-expressed in metastatic prostate cancers (67). Additionally, Horvath et al. found that the subset of primary prostate cancers that retain expression of ERp are significantly more likely to recur after treatment (92). Taken together, these observations suggest that loss of ERp expression is important for the progression of primary prostate cancer to higher grade, but lesions that retain ERp expression very late in the primary prostate cancer may metastasize or recur. However, the precise role of the estrogen receptors in the development of primary and metastatic prostate cancer still requires much clarification.

In summary, CGI hypermethylation patterns in metastatic prostate cancers are largely similar to those in primary prostate cancers. Indeed, it appears that the CGI hypermethylation changes found in metastases are already present in a large portion of primary prostate cancer cells. That is, at least from a CGI hypermethylation perspective, the predilection for developing metastasis is already coded for in the primary prostate cancer lesions. These patterns are then maintained in an almost clonal manner even through the process of invasion and metastasis. We will now examine how these observations may be integrated to understand how these CGI hypermethylation changes are initiated, maintained and propagated during the process of prostate carcinogenesis and cancer progression.

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