ReviewMolecular Detection of Prostate Cancer: A Role for GSTP1 Hypermethylation
Introduction
Over the last two decades, prostate cancer has become a major health issue in Western countries. Excluding cutaneous malignancies, prostate cancer stands as the most frequent malignant illness in men and the second leading cause of cancer-related mortality [1]. For the year 2004 in the United States, it is estimated that 230,110 men will be diagnosed with prostate cancer (accounting for one third of all new cancer cases in men), and 29,900 will die from this disease [1]. Although several risk factors and protective agents have been reported no adequate prophylactic measures are presently available. Therefore, the effective management of this disease relies on early detection. Whereas curative treatment (radical prostatectomy or radiotherapy) is feasible for patients with the earliest stage disease [2], [3], locally advanced or metastatic disease carries a poor long-term prognosis due to the notable lack of curative therapy [4].
This review will focus on the rationale for development of molecular assays for the early detection of prostate cancer, emphasizing the role of the identification of epigenetic alterations as a promising strategy to attain that goal.
Section snippets
Is there a need for molecular detection of prostate cancer?
The progressive use of serum prostate specific antigen (PSA) level as a screening tool, in addition to digital rectal examination (DRE) and transrectal ultrasonography, increased the ability to detect prostate cancer while still organ-confined [5], and may account for the decreasing mortality rate related with this disease [1]. However, serum PSA has limited diagnostic value because the sensitivity and specificity of the test is at best 75% [6]. Although elevated serum PSA levels (greater than
Molecular markers for prostate cancer: genetics vs. epigenetics
Cancer is a multistep process involving the accumulation of genetic alterations that transform normal into abnormal cells, characterized by uncontrolled growth, invasion and systemic spread. Thus, the identification of genetic alterations that underlie malignant transformation might provide an effective tool for early cancer detection. DNA-based markers offer many advantages because they enable the analysis of clinical samples in a high-throughput fashion [16]. This approach allowed for the
Epigenetic alterations: an emerging class of cancer biomarkers
Epigenetics may be defined as the inheritance of information based on gene expression levels, in contrast to genetics, i.e., transmission of information based on gene sequence [27]. Methylation of the cytosine nucleotide residue located within the dinucleotide 5′-CpG-3′ is the most frequent epigenetic alteration in humans. These CpG dinucleotides are not randomly distributed in the genome. Instead, there are CpG-rich regions - “CpG islands” – frequently associated with the 5′ regulatory regions
Selecting a method for detection of hypermethylation in the clinical setting
The use of methylation markers for cancer detection requires technologies displaying high sensitivity and specificity, reproducibility, homogeneity and high-throughtput capabilities. Of the several assays that have been developed for the characterization of DNA methylation, those based on the analysis of sodium bisulfite conversion of template DNA seem to be the most appropriate for clinical use because they require very small amounts of DNA. The sodium bisulfite treatment of DNA converts
GSTP1 hypermethylation: a paradigm for molecular detection of prostate cancer
Glutathione-S-transferases (GSTs) comprise a family of enzymes involved in DNA protection from electrophilic metabolites of carcinogens and reactive oxygen species by conjugating chemically reactive electrophiles to glutathione [57]. In prostate cancer, loss of expression of the glutathione-S-transferase P1 enzyme (GSTP1) is a frequent finding and GSTP1 silencing is directly associated with promoter hypermethylation [58], [59], [60], [61]. This event is the most frequent somatic genome
Methylation profiling of prostate cancer
Since QMSP for GSTP1 allows the detection of 80–90% of prostate adenocarcinomas, with perfect specificity, a broader quantitative description of genes hypermethylated in prostate cancer might provide additional molecular markers that could increase the detection rate and provide relevant information for pathological assessment and clinical management.
Gene promoter methylation profiles in prostate cancer have been published [79], [80], in addition to the more numerous repertoire of single gene
Future prospects
Contrarily to genetic alterations, like mutations and deletions that permanently and definitively change DNA sequence, CpG methylation is a potentially reversible modification. Hence, promoter methylation is amenable for therapeutic intervention aimed at reactivating epigenetically silenced cancer genes, with an increased likelihood of success when compared to experimental gene therapeutic approaches. In prostate cancer cell lines, demethylation of GSTP1 is feasible and it is accompanied by
Acknowledgement
R.H. and C.J. are supported by grants from Liga Portuguesa Contra o Cancro – Núcleo Regional do Norte and Fundação para a Ciência e Tecnologia (SFRH/BPD 8031/2002 and POCTI/CBO/38853/2001), Portugal, respectively.
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