Molecular genetics of prostate cancer: emerging appreciation of genetic complexity

The emergence of Next Generation Sequencing is providing novel insights into cancer genomes as part of large-scale efforts by the International Cancer Genome Consortium (ICGC), as well as individual Genome Centers. Studies performing whole genome or whole exome DNA sequencing are remarkable both for the alterations discovered and equally important for the infrequent nature of recurrent mutations. Current understanding of the prostate cancer (PCa) genome is based on extensive RNA-sequencing for novel gene fusions and the first whole genome sequencing effort. The emerging data suggest that there are few recurrent genetic mutations. Surprisingly, the PCa genome undergoes frequent large-scale genomic rearrangements that could not have been predicted using previous DNA sequencing approaches, or even whole exome sequencing approaches. These large-scale rearrangements appear not to occur randomly, but demonstrate patterns leading to the 'chained' juxtaposition of known oncogenes. Future efforts in DNA sequencing will help to determine the recurrent nature of these genomic rearrangements, their association with other alterations and their effect on PCa disease progression. These discoveries raise the possibility that PCa might soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogeneous subtypes identifiable by molecular criteria, and perhaps vulnerable to targeted therapies.