Genomic and phenotypic heterogeneity in prostate cancer

Abstract

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care. This Review summarizes the manifestations of inter-tumoural and intra-tumoural heterogeneity in primary and metastatic prostate cancer, emphasizing the contribution of genomics studies and discussing the importance of phenotypic changes. The authors also critically discuss the implications for clinical management and research. Primary prostate cancers are often multifocal with spatial and morphologically distinct tumour foci. Individual tumour foci can show non-overlapping truncal genomic alterations, suggesting that multiple clonally distinct cancers can arise in a given patient. Intra-tumoural and inter-tumoural heterogeneity present within the prostate gland poses diagnostic challenges. Despite the multiclonality of primary cancer, clonal bottlenecks imposed by the metastatic process and further by therapeutic interventions seem to select for a single dominant clone in lethal metastatic prostate cancer.