Prostate cancer is the most frequently diagnosed cancer in males in many developed countries, with, for example, about 30,000 new cases diagnosed annually in the UK and over 150,000 in the US. Its prognosis is very variable; although many thousands of men live with indolent prostate cancer for many years before dying of other causes, most diagnosed with metastatic disease will eventually die from their cancer. There are no curative options for these patients, although androgen deprivation through surgery or treatment with drugs such as goserelin is often temporarily effective.

There is, therefore, a need for novel targets for drugs for metastatic prostate cancer, and thus for more information about the genetic basis of the disease. A large group of mainly US-based researchers led by Levi Garraway at the Broad Institute of Harvard and MIT, Cambridge, MA, USA has now sequenced the complete genomes of seven primary prostate tumours and paired normal tissue to investigate the extent of genetic changes in these tumours. This is the first study in which whole-genome sequencing of tumours, still a relatively new technique, has been applied to prostate cancer.

Garraway and co-workers performed paired-end, massively parallel genome sequencing on tumour and matched normal DNA taken from seven prostate cancer patients using second-generation Illumina technology. All tumours were of stage 2c or higher, and Gleason grade 7 or higher, indicating metastatic disease. The sequences revealed a wide range of all types of genomic alteration. The average observed mutation rate of 0.9 point mutations per megabase of DNA was similar to rates observed in acute myeloid leukaemia and breast cancer, but lower than some other tumour types; the median number of non-synonymous mutations in protein coding genes was 20. Two known cancer-related genes – SPTA1 and SPOP – were mutated in two out of the seven tumours. Mutations were also found in several tumours in proteins in the HSP-1 stress response complex, and in those known to be involved in antigen presentation and processing. The latter finding is particularly interesting because prostate cancer can often be successfully treated with immunotherapy.

Chromosome rearrangements were very common in the tumour genomes, with a median of 90 per genome being observed. Rearrangements, like mutations, varied considerably between tumours, but, also like mutations, they were often observed within or near known cancer genes. Three genes known to be involved in cancer – ZNF407, a zinc finger; the tumour suppressor PTEN; and the chromatin modifier CHD1 – were disrupted by rearrangements and non-synonymous mutations in different samples. Other genes found to be involved in rearrangements in two or more tumours included CADM2 and MAGI2, which has not previously been implicated in prostate cancer but which is known to interact with PTEN. Many of the observed rearrangements were “balanced” or “copy-neutral” with no DNA gain or loss.

Three of the tumours harboured a series of rearrangements that led to a fusion between two genes, TMPRSS2 and ERG.  These tumours also had slightly different rearrangement patterns from the others away from this locus; in particular, TMPRSS2-ERG positive tumours had more breakpoints in open chromatin regions and TMPRSS2-ERG negative ones had more in closed chromatin regions. This suggests that the genomic alterations that lead to prostate cancer can be linked to chromatin changes. Although these results confirm that there is a great variety in the genetic aberrations that can lead to metastatic prostate cancer, they highlight some common pathways, particularly chromatin re-modelling and the HSP-1 stress response, which may provide useful targets for new drugs against this disease.

Reference

Berger, M.F., Lawrence, M.S., Demichelis, F. and 38 others (2011). The genomic complexity of primary human prostate cancer. Nature 470, 214-219. doi: 10.1038/nature09744