Integrated genome and transcriptome sequencing identifies a novel case of hybrid and aggressive prostate cancer

Next generation sequencing is making sequence-based molecular pathology and personalised oncology viable. We selected an individual initially diagnosed with conventional, but aggressive, prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and genomic architecture were remarkably homogeneous, yet it was possible to determine the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogenous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but private gene fusions, including C15orf21:MYC, recapitulated this biology while the amplification and over expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and conceivably a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology, and personalized oncology. 5 samples