The mutational landscape of prostate cancer

Abstract

Context: Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity that may underlie the variable clinical course of the disease.

Objective: In this review, we discuss the common genomic alterations that form the molecular basis of PCa, their functional significance, and the potential to translate this knowledge into patient care.

Evidence acquisition: We reviewed the relevant literature, with a particular focus on recent studies on somatic alterations in PCa.

Evidence synthesis: Advances in sequencing technology have resulted in an explosion of data regarding the mutational events underlying the development and progression of PCa. Heterogeneity is the norm; few abnormalities in specific genes are highly recurrent, but alterations in certain signaling pathways do predominate. These alterations include those in pathways known to affect tumorigenesis in a wide spectrum of tissues, such as the phosphoinositide 3-kinase/phosphatase and tensin homolog/Akt pathway, cell cycle regulation, and chromatin regulation. Alterations more specific to PCa are also observed, particularly gene fusions of ETS transcription factors and alterations in androgen signaling. Mounting data suggest that PCa can be subdivided based on a molecular profile of genetic alterations.

Conclusions: Major advances have been made in cataloging the genomic alterations in PCa and understanding the molecular mechanisms underlying the disease. These findings raise the possibility that PCa could soon transition from being a poorly understood, heterogeneous disease with a variable clinical course to being a collection of homogenous subtypes identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies.

Keywords: Copy number aberrations; Genomics; Oncogene; Sequencing; Tumor suppressor.

Figure 1

Molecular Classification of Prostate Cancer. (A) The majority of primary prostate cancers harbor ETS gene rearrangements, most commonly as TMPRSS2-ERG fusions. The PTEN and TP53 tumor suppressors are deleted or mutated in 20-40% of primary prostate cancer, with significant overlap with each other and ETS rearrangements. SPOP mutations, which occur in about 10% of prostate cancers, are mutually exclusive with ETS rearrangements, relatively lack PTEN deletions and other lesions, but are associated with deletions of CHD1. (B) Metastatic tumors have a significant increase in lesions in PTEN and other PI3K pathway components and an overall increase in genomic aberrations; in addition, mutations and amplifications of the AR gene emerge, mostly in cancers treated with androgen deprivation therapy.