The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing

Abstract

Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer 'omics', including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.

Figure 1

Significantly recurrent molecular alterations in prostate cancer. Circos plot showing the 90 significantly aberrant copy number aberrations from an analysis of 372 prostate tumours (green=loss; red=gain). Significantly mutated genes from studies of large tumour cohorts are annotated by black dots around the outside, with dot size proportional to the level of significance.^, Recurrent fusion genes involving ETS transcription factors are shown in the centre of the plot, as are recently identified non-ETS fusions genes.^,,,,

Figure 2

Chromothripsis generates complex genomic rearrangements which can be oncogenic. During chromothripsis tens to hundreds of breakpoints (indicated by arrowheads) can form in a single chromosome arm, generating fragments of DNA. These fragments are then incorrectly repaired through NHEJ, resulting in the fusion of multiple genes and the loss of genes including tumour suppressors. Double minute chromosomes containing oncogenes can also be formed and subsequently amplified. Transcription across reconstituted fragments of genes can result in poly-gene fusion transcripts, which may be a transcriptomic signature of chromothripsis. NHEJ, non-homologous end joining.

Figure 3

The hybrid adenocarcinoma-neuroendocrine prostate tumour hypothesis. A growing body of evidence suggests that the differentiated cells of the adult prostate (luminal, basal and neuroendocrine) share a common progenitor (top panel). It is traditionally thought that adenocarcinoma arises directly from mutation of luminal cells, although basal cell-of-origin models also exist (bottom panel). Neuroendocrine tumours can arise directly from mutation of neuroendocrine cells, or via a transdifferentiation mechanism from adenocarcinoma, induced by, e.g. androgen deprivation therapies. However, the novel hybrid adenocarcinoma-neuroendocrine tumour we identified is difficult to reconcile with any of these observations leading to the hypothesis that it arose from a progenitor-like cell that possesses properties of both luminal and neuroendocrine cells. PCa, prostate cancer.