Abstract
Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.
Highlights
Prostate cancer is the most frequently diagnosed nonskin cancer and second most common cause of cancer-related deaths in men, with an estimated 1,600,000 cases and 366,000 deaths annually
Bottcher and coworkers have explored the genomic features of cribriform/IDC (CR/IDC) prostate cancers of patients analyzed in the context of the Cancer Genome Atlas Project (TCGA) and the Canadian Prostate cancer genome Network (CPC-GENE): CD-IDC frequency was present in 31% of TCGA and 38% of CPC-GENE datasets; CD/IDC presence was associated with deletions of 8p, 16q,10q23, 13q22, 17p13, 21q22, and amplification of 8q24; the most relevant copy number alterations affect some genes associated with aggressive prostate cancer, such as loss of PTEN, CDH1, and BCAR1, and gain of MYC; point mutations of TP53, speckle-type PO2 protein (SPOP), and Forkhead box A1 (FOXA1) are associated with CR/IDC, but occurred less frequently than copy number alterations [31]
This study showed that 13 genes were recurrently mutated in prostate cancer, in addition to previously reported recurrent mutations: deletions of SPOP, TP53, FOXA1, PTEN, MED12, and CDKN1B; additional clinically relevant genes were identified with lower frequencies, including BRAF, HRAS, AKT1, CTNNB1, and ATM (Figure 1) [38]
Summary
Prostate cancer is the most frequently diagnosed nonskin cancer and second most common cause of cancer-related deaths in men, with an estimated 1,600,000 cases and 366,000 deaths annually. This treatment is often followed by recurrent androgen-independent prostate cancer, with frequent metastases. Three stages of development of human prostate tumors have been identified: (a) intraepithelial neoplasia that can be considered a precancerous state, characterized by hyperplasia of luminal cells and progressive loss of basal cells; (b) adenocarcinoma androgen-dependent (subdivided into two stages, adenocarcinoma latent and clinical), characterized by the complete loss of basal cells and the strong luminal phenotype: at this stage, the tumor is androgen-dependent and its growth can be controlled by androgen deprivation; and (c) adenocarcinoma androgen-independent (or castration resistant) that represents the evolution of adenocarcinoma and does not depend for its growth by androgens. The luminal compartment expands, and basal cells are lost. This corresponds to a luminal phenotype both at immunophenotypic and genotypic levels. Late stages of disease, characterized by castration-resistant prostate cancer and by the development of metastases, enrich for basal cell genes and stem cell genes
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