Mini-reviewMolecular alterations in prostate cancer
Introduction
Prostate cancer is a highly heterogeneous disease, both in terms of its pathology and clinical presentation. It is the second leading cause of cancer-related deaths in Western males, yet because prostate tumors can take decades to progress to clinically significant disease, they are difficult to diagnose and treat. Latent prostate cancer is common, with many older men showing localized prostate tumors upon autopsy that died from other causes [1]. In contrast, once metastasis has been detected by imaging, the vast majority of patients will likely die from prostate cancer. Over the past two decades, serum PSA screening has provided a valuable tool for prostate cancer surveillance, however the age-adjusted incidence of mortality has remained relatively constant, therefore new tools are needed to guide prognosis and treatment.
Research into the genetic origins of prostate cancer has accelerated dramatically in recent years, aided by the availability of new high-throughput microarray and sequencing technologies. Numerous gene expression studies have been conducted to characterize prostate cancer initiation and progression, and many of them have shown correlation with clinical outcome. However, molecular associations with prostate cancer phenotypes continue to be fragmentary, and in some cases are poorly substantiated by follow-up investigations [2]. Early studies that profiled cancerous versus benign tissues have now been supplemented by micro-dissection procedures, revealing differences in gene expression patterns across individual tumor foci isolated from the same specimen [3]. Guided by such observations, investigators are now directing their attention to underlying molecular features that could be associated with gene expression alterations, toward a more comprehensive understanding of prostate cancer initiation and progression. These include genetic polymorphisms and epigenetic modifications, alternative splicing, and post-translational regulation involving non-coding RNA. This review surveys studies that have been conducted in each of these areas.
Section snippets
Gene expression profiling in prostate cancer
Shortly following the introduction of gene expression microarray technologies, a number of early profiling studies were reported using prostate cancer tissues and tumor-derived cell lines [4], [5], [6], [7], [8]. Such early studies successfully identified genes in key regulatory pathways that are widely associated with cancer phenotypes, for example genes involved in cell cycle regulation, DNA replication, and DNA repair [9]. Singh et al. was the first group to show a correlation between gene
Somatic mutations
Gene expression heterogeneity in prostate cancer is perhaps not very surprising considering the numerous types of chromosomal abnormalities that have been described, including chromosomal insertions, deletions, amplifications, and translocations [19], [20], [21], [22], [23], [24], [25]. Genomic instability is an underlying characteristic of prostate carcinoma transformation. Nearly all solid tumors are genetically unstable, and it is now widely accepted that cancer results from the accumulation
Epigenetic modulation
Epigenetic modulations allow transmission of cellular traits without changes in genomic sequence. They appear to be sensitive to a variety of environmental factors that have been associated with prostate cancer progression, such as diet and oxidative stress [53]. The most widely studied epigenetic alterations in cancer include histone modifications and DNA methylation [54]. Their potential application in the diagnosis, disease progression and treatment of prostate cancer has been the subject of
Alternative splicing
Alternative splicing, the process by which exons of pre-mRNAs are spliced in different arrangements, plays a major role in the functional diversity of expressed gene transcripts. This came to be appreciated early this decade when expressed sequence tag (EST) databases such as Unigene predicted on the order of 120,000 human gene bins, whereas early drafts of human genomic sequences predicted only about 25,000–30,000 protein encoding genes. EST sequences can now be aligned to genomic sequences
Other post-transcriptional modulators
Recent estimates indicate that protein encoding genes comprise only about 2% of the human genome, however, tiling microarray experiments have shown that over 50% of the genome is transcribed to RNA [84]. The majority of these transcripts are termed non-coding RNA (ncRNA), the sub-categories of which have been reviewed recently [85]. Non-coding RNAs appear to play important regulatory roles in cellular processes, although many of the mechanisms are not yet understood. For example, Louro et al.
Discussion
As illustrated throughout this review, expression patterns for prostate-cancer-causing genes can be modulated through a variety of different mechanisms (Fig. 2). Furthermore, the original concept of an oncogene has taken on new meaning with the elucidation of somatic mutations and alternative splicing events that result in subtle or even gross differences in protein function. Despite these observations, a number of important oncogenic gene pathways have been elucidated over the past several
Acknowledgements
Thanks to Lyle Arnold for his intellectual contributions and suggestions, and also to Steve Brentano, Matthias Jost, and Harry Rittenhouse for their critical edits and suggestions.
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