Prostate Cancer molecular biology and genetics

Research into prostate cancer genetics aims to improve our understanding of men’s risk of disease and the factors that drive cancer progression. This knowledge has the potential to improve diagnosis and guide the development and use of targeted treatments.

Prostate cancer often clusters in families and 5-10% of all prostate cancers may have a substantial inherited component. Searches for high-risk prostate cancer loci have identified the familial breast cancer gene BRCA2 as an important susceptibility factor. Carriers of germline mutations in BRCA2 have at least five times greater risk of prostate cancer and frequently develop a more aggressive form of the disease. 1, 2

The current IMPACT study is evaluating the benefits of PSA screening in this high-risk population. 3 However, BRCA2 mutations account for only 2% of all early-onset cases (<55years) indicating that further susceptibility loci exist. 1 Mutations in the BRCA1 gene have a smaller effect, increasing a man’s risk of prostate cancer by less than two-fold. 4

Current evidence indicates that prostate cancer inheritance is complex with numerous lower-penetrance gene variants contributing to disease progression. Several studies highlight ELAC2, MSR1 and RNASEL as candidate genes for hereditary prostate cancer. 5 MSR1 and RNASEL encode proteins involved in innate immunity, which fits well with the recent hypothesis that inflammation plays a key role in prostate carcinogenesis. 6 The International Consortium for Prostate Cancer Genetics has also identified a novel susceptibility locus on chromosome 22. 7

Genetic variants common in the wider population may also contribute to sporadic cases of prostate cancer. For example, single nucleotide polymorphisms (SNPs) in the Androgen Receptor(AR) gene, inflammatory-related genes and hormone metabolising genes have all been linked to increased risk of disease. 8, 9 Strong evidence also links polymorphisms on chromosomes 8 and 17 with prostate cancer and a combination of five of these SNPs can increase an individual’s risk by more than five-fold. 10

Three large international studies have identified a further 10 important prostate cancer susceptibility loci and highlighted candidate genes within these regions that may contribute to this disease including MSMB, KLK3 and LMTK2. 11-13

In addition to germline faults, mutations in key oncogenes and tumour suppressor genes have been detected in prostate cancer cells per se, including amplification of MYC and loss of NKX3.1, TP53, CDKN1B and PTEN. 14 Chromosomal translocations have also been found to fuse 5’ regulatory elements of genes upstream of ETS transcription factors. 15, 16 Epigenetic events such as DNA hypermethylation affect the expression of several genes in prostate cancer including GSTP1, a gene involved in carcinogen detoxification. 17 This alteration occurs in nearly all prostate cancers and may prove useful as a diagnostic marker.

Much research is now focussing on the faulty molecular pathways that contribute to prostate cancer progression. AR signalling in particular, plays a crucial role at different stages of the disease. Overexpression and mutation of the AR gene can alter both the ligand sensitivity and specificity of the receptor. These changes frequently underlie the onset of androgen-independent disease that fails to respond to hormone deprivation strategies. Alterations to other pathways involving PI3K, ERBB2 and BCL2 are also linked to the transition to hormone-independence. 18, 19

Genetic profiling is likely to become more important in the future providing valuable prognostic information and guiding the use of different treatment options. Patients with two copies of the TMPRSS2-ERG fusion gene have been linked with worse prognosis. 20 Key genes such as LMTK2 are also being considered as targets for novel prostate cancer treatments.