The identification of genetic susceptibility loci for prostate cancer has been extremely difficult. It was only in 1996 that the first prostate cancer susceptibility locus, HPC1, was mapped to chromosome 1q24–25, which was subsequently identified as the RNaseL gene. RNaseL is a uniquely regulated endoribonuclease requiring 5′-triphosphorylated, 2′,5′-linked oligoadenylates (2–5A) for its activity. This enzyme is important in immune response to viral infection, induction of apoptosis, and cell cycle and cell differentiation regulation. The presence of germ-line mutations in RNaseL that segregate with disease within hereditary-prostate-cancer-affected families and the loss of heterozygosity (LOH) in tumor tissues suggest a relationship between innate immunity and tumor suppression.

RNaseL mutations have an autosomal dominant type of inheritance with high penetrance; consequently, carriers of this mutant variant have a high risk of prostate cancer development [4]. The HPC1 locus is associated with disease that affects younger men (age < 66 years) and multiple family members [12]. Men with this predisposition typically have more aggressive cancer (higher Gleason score), often locally advanced or even metastatic. Germ-line mutations in the tumor-suppressor gene RNaseL have been reported to track in PCa families, and have been implicated in up to 13 % of all prostate cancer cases [13].

The ElaC2/HPC2 gene at 17p11.2 is the first candidate gene identified for human prostate cancer based on linkage analysis and positional cloning [14]. HPC2 gene encodes ElaC protein 2, a zinc phosphodiesterase located in the nucleus. ElaC2 displays transfer ribonucleic acid (tRNA) 3′-processing endonuclease activity, inducing tRNA maturation. The ELaC2/HPC2 gene displayed several sequence variants: missense mutations Ser217Leu, Ala541Thr, and Arg781His and a frame-shift mutation 1641 insG [14]. Two previous studies found an association between Ser217Leu and Ala541Thr and their combination with PCa [14, 15].

The finding of a nonsense mutation in the HPC2/ELaC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, HPC2/ELaC2 germ-line mutations are rare in hereditary prostate cancer and variants Leu217 and Thr541 do not appear to influence the risk for hereditary prostate cancer, suggesting that alterations within the HPC2/ELaC2 gene play a limited role in genetic susceptibility to hereditary prostate cancer [16].

The MSR1 gene at 8p22–23 has been implicated as a candidate gene for hereditary prostate cancer. MSR1 encodes membrane glycoproteins, MSR type-I and type-II, involved in the modulation of interaction between foreign cells and macrophages, cell adhesion and phagocytosis, arterial wall deposition of cholesterol during atherogenesis, and endocytosis of low density lipoproteins. The frequencies of deleterious alleles is low, and the penetrance is apparently moderate, suggesting that MSR1 is not a major susceptibility gene in prostate cancer families [17]. Meta analysis of existing data has failed to show any clear correlation between the MSR1 locus and the hereditary risk of prostate cancer [18].

HOXB13 is a transcription factor gene important in prostate development. HOXB13 is suppressed in AR negative prostate cancer cells and its overexpression results in significant inhibition of cell growth. In addition, HOXB13 has been shown to suppress androgen-stimulated AR activity by interacting with the receptor [19].

A recurrent germ-line mutation (G84E) in the HOXB13 has been recently identified by Ewing et al. in a previously recognized region of linkage at 17q21–22 as harboring an increased risk for familial prostate cancer [20]. Xu et al. have utilized a large sample of prostate cancer-prone families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG) to confirm that the HOXB13 G84E mutation is rare, but significantly associated with predisposition to PCa. G84E mutation was present in ~ 5 % of prostate cancer families, predominantly of European descent, and was encountered more frequently in males diagnosed with PCa (51 %) than in unaffected male family members (30 %) [21]. The frequency of the mutation was higher in PCa patients with early-onset disease (age at diagnosis ≤ 55 years, 2.2 %) or with positive family history (2.2 %), and most common in patients with both features (3.1 %). In a family-based analysis, the proportion of G84E mutation-associated PCa was highest in families from the Nordic countries of Finland (22.4 %) and Sweden (8.2 %), particularly for early-onset PCa and cases with substantially elevated prostate-specific antigen (PSA) [22]. HOXB13 G84E variant poses a statistically significant risk of hereditary PCa, while accounting for only a small fraction of all prostate cancers.

An indeterminate number of weak candidate susceptibility loci have been suggested to be involved in hereditary PCa (Table 8.1). However, high-risk PCa alleles, associated with a lifetime penetrance of at least 66 %, have a frequency unlikely above 2–3 % of the cases, whereas low-risk PCa alleles may have a more frequent impact on sporadic PCa.

Several epidemiological studies have shown a possible, either synchronous or metachronous association of different tumors (e.g., breast, brain, gastrointestinal tumors, and lymphomas) with PCa, thus suggesting common genetic risk factors.

Conversion of testosterone to dihydrotestosterone (DHT), its active metabolite on prostatic target cells, is catalyzed in prostatic tissue by the enzyme 5-α-steroid-reductase (srd5α). The two genes srd5α1 and srd5α2, encoding for srd5α isoforms type I and type II, are located on chromosomes 5p15 and 2p23, respectively. It is believed that isoform type II predominates in the prostate. A larger number of dinucleotide thymine-adenine (TA) repeats (≥ 18) on the last exon of the srd5α2 gene (locus 2p22–23) is common in African-American men, and seems to confer an increased PCa predisposition [46].

AR is encoded by a gene located on the short arm of chromosome X (Xq11–12). This locus is one of the most conserved regions of the human genome, with only very rare mutations occurring at this site [47]. One of the critical functions of the product of the AR gene is to activate the expression of target genes. This activity resides in the transcriptional N-terminal domain of the protein, which is encoded in exon 1 and contains polymorphic guanine-guanine-cytosine (GGC) and cytosine-adenine-guanine (CAG) repeats. The variability in the AR gene length is determined by polymorphisms in the N-terminal region. A smaller number of either GGC (< 16) or CAG (< 18) repeats appears to be associated with a higher level of AR activity, resulting in an increased PCa risk [48]. The number of CAG and GGC base triplet repetition in the first exon of the AR gene is substantially lower in African-American than in Caucasian men [4, 49].

Loss of chromosomal Y segment is the most common chromosomal alteration that may be identified in prostate cancer tissue. Sex-related gene on chromosome Y ( SRY) is downregulated in PCa. Since SRY acts as negative regulator of AR, the loss of chromosome Y results in an increase in prostate cancer growth [50].