Somatic Changes In Prostate Cancer

While some tumors may contain inherited mutations, all tumors contain acquired or somatic alterations. Advances in the techniques used to examine these changes resulted in the identification of chromosomal regions deleted or amplified that may play a role in tumorigenesis. Chromosomal changes have been identified in specific stages of disease progression with the average number of alterations per case significantly higher in distant metastases than primary tumors.51 As the technology improves, specific gene sequences and their protein products are being analyzed, which will improve our understanding of the mechanism of disease. It is hoped that our improved understanding will enable biomarkers to be developed, which will enable more accurate prediction of patient outcome as well as act as targets for drug treatments.

One of the most widely used techniques for examining chromosomal alterations is comparative genomic hybridization (CGH). This allows the detection of DNA sequence copy number changes throughout the genome and can, therefore, identify regions where deleted TSG or amplified oncogenes may be harbored. Researchers in Finland have used this technique and shown that locally recurrent hormone refractory prostate cancers contain almost four times as many alterations than the untreated primary tumors.52 Their findings are summarized in Table 11.2 and suggest the early development of prostate cancer is as a result of inactivation of TSG, whereas later progression, including the development of hormone refractory disease, is associated with oncogenic activation (Fig. 11.1).

CGH and LOH (loss of heterozygosity) studies have demonstrated the most common chromosomal aberrations in prostate cancer are deletions in chromosome regions 3p, 6q, 7q, 8p, 9p, 10q, 13q, 16q, 17q and 18q and gains in 7p, 7q, 8q and Xq.3'51'54-57 The important alterations and putative critical gene changes to date will be discussed, in particular where they are believed to alter the pathogenesis of prostate cancer.

Early genetic changes

Hypermethylation of the GSTP1 gene is seen in 70% of cases of high-grade PIN (HGPIN) and over 90% of prostate cancers, but is a rare event in benign prostate tissue.58,59 The GSTP1 gene on 11q13, encodes for glutathione S-transferase, which conjugates electrophilic and hydrophobic environmental carcinogens with glutathione, thus protecting the cell.60 Hypermethylation of the CpG islands of the promoter region prevents the transcription of the gene, thus removing the cell's in-built protection mechanism against potential environmental carcinogens, including dietary factors.47 As GSTP1 inactivation occurs in the vast majority of cases of HGPIN and prostate cancer early in the disease course, it may be used, in the future, as a molecular marker.62 Indeed, studies have already reported measurement of GSTP1 methylation in cells in the urine of men with prostate cancer.61,62 Cairns etal. detected GSTP1 methylation in the urine of 27% of patients with GSTP1 methylation in their primary tumor.61 Goessl et al. improved the sensitivity of this technique to 73% by looking at GSTP1 methylation in the urine sediment after prostatic massage. They found GSTP1 methylation in 1 (2%) of 45 patients with BPH, 2 (29%) of 7 patients with HGPIN, 15 (68%) of 22 patients with localized prostate cancer and 14 (78%) of 18 with locally advanced or disseminated disease.62 Furthermore, augmentation of GST activity, using pharmaceutical GST inducers, may have a role in prostate cancer prevention.63

Two of the most common deletions found using CGH are on 8p and 13q.64 Other laboratory techniques including

Table 11.2. Chromosomal changes associated with the progression of prostate cancer during hormonal therapy. Reproduced from Nupponen and Visakorpi (1 999).56

Tumors showing alteration (%)

Minimal region

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