ABSTRACT
Prostate-specific antigen (PSA) and its molecular derivatives have revolutionized the detection, diagnosis, and clinical management of prostate cancer (CaP), however, this tumor marker currently is positive in cases that are cancer-free in approximately 75% of the biopsy cases.1,2 In spite of major advances in PSA technology, including assays for complex PSA, free PSA, proPSA (–2, –5, and –7 truncated forms), only limited improvements in the specificity for detection of prostate cancer have been demonstrated.2-5
A molecular assessment of biomarkers in oncology has been derived from the definition of clonal epigenetic and genetic alterations identified as DNA sequence alterations, changed RNA, and/or protein differential expression in preneoplasia and histologic progression in cancer.6 Several studies have demonstrated that transformation of a normal cell into a malignant cell requires a series of genetic changes (or “hits”)7-11 such as point mutations, DNA methylation events in promoters or exons, chromosome deletions, insertions, amplifications, and translocations.12-14
Additionally, several classes of well-characterized nuclear organelles (spliceosomes, centrosomes, telomeres, and nucleosomes), gene families (High Mobility Group Proteins (HMGA), ATPase chromatin remodeling complex (SWI/SNF), retinoid acid receptors (RARs), matrix associated receptors (MARs), etc.), and key structural and regulatory proteins (e.g., nuclear matrix proteins, HMGA proteins, nuclear histones H1, H2A, H2B, H3, and H4, and SWI/SNF complex) have been identified as being important to the maintenance of nuclear chromatin structure, transcription, and cell
function in cancer.15-22 Given the general spectrum of molecular events that are known to occur during premalignant and malignant transformation and metastasis, numerous alterations in several pathways have been observed providing considerable opportunities to identify new biomarkers in prostate cancer using blood and urine markers.23-25
In the field of prostate cancer, the benefits of the advances in molecular biology of carcinogenesis have reaped major improvements in our current understanding of prostate cancer etiology and molecular pathogenesis and have identified the importance of hereditary (genetic susceptibility), epigenetics, and somatic gene defects that are responsible for the development and progression of this disease.26-29 Human prostate cancer (HPC) susceptibility genes have been described on chromosome 1q24-25 (HPC1), 1q42-2-q43 Predisposing for Prostate Cancer (PCaP), 1q36 (CARB), 16q23.2, 17p11 (HPC2), 20q13 (HPC20) and chromosome Xq27-28 (HPCX).29 The HPC1 gene has been cloned (RNASEL), and the HPC2 gene (ELAC2) has also been cloned. Key susceptibility genes that appear to be important in the host response to infections and inflammation are the macrophage scavenger receptor (MSR) on chromosome 8p22 and RANSEL on chromosome 1q24-25 (HPC1). Also, several polymorphic variants of three genes (androgen receptor (AR), cytochrome p450 (CYP17), and Steroid 5-Alpha-reductase 2 (SRD5A2), which have suggested a role for viral or bacterial infections as well as chronic inflammation in the development of prostate cancer.26
