Elsevier

European Urology

Volume 46, Issue 5, November 2004, Pages 660-669
European Urology

Review
Molecular Detection of Prostate Cancer: A Role for GSTP1 Hypermethylation

https://doi.org/10.1016/j.eururo.2004.06.014Get rights and content

Abstract

Objective:

Prostate cancer is a leading cause of cancer-related mortality and morbidity in Western world. Curative treatment is feasible provided the disease is diagnosed in its earliest stages, but current screening methodologies are characterized by low specificity. DNA-based markers are a class of new and promising tools for cancer detection. Promoter hypermethylation is a common epigenetic alteration affecting cancer-related genes.

Methods:

We critically reviewed the most relevant reports on prostate cancer detection using DNA methylation analysis in prostate tissue and body fluids.

Results:

The epigenetic silencing of the glutathione-S-transferase P1 (GSTP1) gene is the most common (>90%) genetic alteration so far reported in prostate cancer. Methylation-specific PCR (MSP) methods allowed for the successful detection of GSTP1 methylation in body fluids (serum, plasma, urine, and ejaculates) from prostate cancer patients. In addition, the development of highly specific quantitative MSP assays augmented standard histopathology for the diagnosis of prostate cancer in tissue biopsies, accurately distinguishing benign from malignant prostate lesions.

Conclusions:

Further advances in the epigenetic characterization of prostate cancer are likely to yield powerful tools for patient diagnosis and management.

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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