Molecular Genetic Etiology of Prostate Cancer

Abstract

Prostate Cancer (PCa) is the most frequently diagnosed non-skin cancer and second leading cause of cancer deaths after lung cancer in the western industrialized countries. It varies widely by geographic location and ethnicity. It is clinically heterogeneous, complex and indeed a multi-factorial disease. While the majority of PCa is sporadic, as much as up to 40% of the cases are associated with some form of genetic susceptibility. It is clear today that etiology of PCa involves several genetic loci with no single major gene accounting for a large proportion of susceptibility to the disease. In particular, allelic variations in four genes, namely RNASEL (1q25), MSR1 (8p22), ELAC2 (17p11) and EphB2 (1p36) have been shown to be associated with increased susceptibility to PCa. Also, tumors harboring mutations in these genes present with more aggressive clinical features and poor outcome. Recently, novel genetic alterations in prostate cancer patients have been identified-these include gene fusions involving the prostate-specific gene transmembrane protease, serine 2 (TMPRSS2) and members of the erythroblastosis virus E26 transforming sequence (ETS) family of transcription factors. This predominant molecular subtype is considered to be an early event in PCa, and emerging evidence demonstrates its potential in prostate cancer detection, stratification and treatment. In addition to gene fusions, there is compelling evidence demonstrating 8q24 region as a prostate cancer susceptibility locus and markers at this locus are statistically significantly associated with an increased PCa risk in different ethnic groups. Genotyping of SNPs / markers in a predefined 8q24 region as well as genome-wide association studies have implicated several polymorphisms (rs7008482, rs1447295, rs16901979, rs698367) in this region as risk factors for PCa. In additions to genetic alterations, frequent epigenetic aberrations such as DNA hypermethylation of tumor suppressor genes has been observed in PCa affecting the expression and function of a battery of genes leading to tumorigenesis, tumor progression and metastasis. In this review, we highlight some of the recent advances in molecular genetic etiology of PCa including promising candidate hereditary PCa susceptibility genes, novel gene fusions in acquired PCa, 8q24 susceptibility locus, as well as examine current literature regarding epigenetic changes leading to prostate cancer development and progression.