Prostate cancer – a biomarker perspective

Despite early detection and reduced risk of death, prostate cancer still remains the second leading cause of cancer death in American men. There is currently no cure for advanced prostate cancer. The multistage, stochastic and highly heterogeneous nature of prostate cancer, coupled with genetic and epigenetic alterations that occur during disease progression and response to therapy, represent fundamental challenges in our quest to understand and control this complex and prevalent disease. Recent advances in drug development and breakthroughs in omics technologies have renewed our efforts to identify novel biomarkers for prostate cancer prognosis, prediction, and therapeutic response monitoring. In this perspective article, we overview the current status and highlight future prospects of biomarkers for prostate cancer, a disease that affects millions of men worldwide

Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.

Abstract Detection, treatment, and prediction of outcome for men with prostate cancer increasingly depend on a molecular understanding of tumor development and behavior. We characterized primary prostate cancer by monitoring expression levels of more than 8900 genes in normal and malignant tissues. Patterns of gene expression across tissues revealed a precise distinction between normal and tumor samples, and revealed a striking group of about 400 genes that were overexpressed in tumor tissues. We ranked these genes according to their differential expression in normal and cancer tissues by selecting for highly and specifically overexpressed genes in the majority of cancers with correspondingly low or absent expression in normal tissues. Several such genes were identified that act within a variety of biochemical pathways and encode secreted molecules with diagnostic potential, such as the secreted macrophage inhibitory cytokine, MIC-1. Other genes, such as fatty acid synthase, encode enzymes known as drug targets in other contexts, which suggests new therapeutic approaches

Molecular genetic analysis of the adenomatous polyposis coli gene region

Familial Adenomatous Polyposis (FAP) is a rare, autosomal dominant predisposition to colorectal cancer, affecting about one in ten thousand individuals in all populations studied. The gene responsible for this syndrome, designated APC (for Adenomatous Polyposis Coli) was mapped to 5q21-q22 by linkage analysis following a cytogenetic report of a male patient with polyposis and an interstitial deletion on 5q. The high incidence of allele loss at 5q21-q22 in carcinomas of sporadic patients suggests that mutation of the APC gene is a very frequent step in the tumorigenic pathway to nonfamilial colorectal carcinomas and emphasises the importance of isolating the gene and identifying its function. Attempts were made to identify this gene using a positional cloning strategy, on the basis of its genomic location rather than by a knowledge of its function. As a first step toward this goal, two approaches were taken to identify a large number of DNA probes mapping within the breakpoints of two, and later three independent deletions encompassing the APC gene. In the first approach, a novel method, termed 'alu-PCR' was developed. By comparing the PCR patterns generated from normal and deleted chromosomes 5, a probe was identified mapping close to the APC gene. In the second approach, genomic libraries constructed from physically dissected DNA around chromosomal region 5q21-q22 were used to derive a large number of DNA probes. These probes facilitated the definition of a new minimally deleted region harbouring the gene and assisted with the construction of a physical map of this region. For the second phase of the cloning project, these DNA probes, in addition to others sub-localised to this region, were used to isolate a collection of yeast artificial chromosomes (YACs) which in total cover some 4-megabase-pairs (Mb) of DNA. Two of the YACs identified in this study, which cover a total distance of 1.1- Mb, were used indirectly to identify potential alterations, particularly small deletions, in homologs of chromosome 5 from FAP patients. One such deletion of 260-kb was identified and shown to be entirely overlapped by one of these YACs. This deletion, and the YAC used to identify it, contain the entire coding sequence of the APC gene

Cdc6 and Cyclin E2 Are PTEN-Regulated Genes Associated with Human Prostate Cancer Metastasis1

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is frequently inactivated in metastatic prostate cancer, yet the molecular consequences of this and their association with the metastatic phenotype are incompletely understood. We performed transcriptomic analysis and identified genes altered by conditional PTEN reexpression in C4-2, a human metastatic prostate cancer cell line with inactive PTEN. PTEN-regulated genes were disproportionately represented among genes altered in human prostate cancer progression and metastasis but not among those associated with tumorigenesis. From the former set, we identified two novel putative PTEN targets, cdc6 and cyclin E2, which were overexpressed in metastatic human prostate cancer and up-regulated as a function of PTEN depletion in poorly metastatic DU145 human prostate cancer cells harboring a wild type PTEN. Inhibition of cdc6 and cyclin E2 levels as a consequence of PTEN expression was associated with cell cycle G1 arrest, whereas use of PTEN activity mutants revealed that regulation of these genes was dependent on PTEN lipid phosphatase activity. Computational and promoter-reporter evaluations implicated the E2F transcription factor in PTEN regulation of cdc6 and cyclin E2 expression. Our results suggest a hypothetical model whereby PTEN loss upregulates cell cycle genes such as cdc6 and cyclin E2 that in turn promote metastatic colonization at distant sites

Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

Nasopharyngeal carcinoma is a malignancy that is prevalent among populations from Southeast Asia. Epidemiological studies indicate that genetic predisposition, Epstein–Barr virus, and environmental conditions may play a role in determining incidence. Molecular studies have implicated a tumor suppressor gene(s) on the short arm of chromosome 3. In this study we provide functional evidence, via monochromosome transfer, for a tumor suppressor gene(s) activity in chromosome 3p21.3