The genomic landscape of prostate cancer

Abstract

Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction, and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.

Keywords: genome sequencing; genomic; prostate cancer.

FIGURE 1

Genomic alterations in four high-risk prostate cancers. Circos plots depicting genomic rearrangements and copy number alterations in four prostate tumors analyzed by whole-genome sequencing (unpublished data). Green and pink lines designate intrachromosomal and interchromosomal rearrangements, respectively. Somatic copy number alterations are indicated in red (amplification) and blue (deletion) in the inner rings. Gleason scores indicate the two most prevalent histologic grades in each tumor. Pathological stage is noted as well, where pT3 indicates locally invasive disease.

FIGURE 2

Somatic alterations in the PI3K pathway in prostate cancer. Selected genes in the PI3K pathway are depicted, alongside the mechanisms by which they are altered in prostate cancer. Putative proto-oncogenes are boxed in red and tumor-suppressor genes in blue. PI3K signaling is frequently activated by deletion of PTEN. PHLPP1 encodes a phosphatase that dephosphorylates activated Akt, and is frequently co-deleted with PTEN in metastatic tumors (Chen et al., 2011). Genomic rearrangements disrupt MAGI2, which encodes a scaffolding protein that stabilizes PTEN (Wu et al., 2000; Berger et al., 2011). Recurrent deletions inactivate the FOXO1A gene, which encodes a transcription factor substrate of Akt that mediates PI3K signaling. Although rare, oncogenic mutations in the receptor tyrosine kinase EGFR or AKT1 may activate the pathway upstream or downstream of PI3K (Cai et al., 2008; Boormans et al., 2010). The expression of most pathway members is dysregulated at the transcript level as well.