Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects

Abstract

Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes ( ERG, PTEN, and SPOP) are recurrently mutated in more than 10% of primary tumors. On the other hand, metastatic castration-resistant tumors have more mutations, but, with the exception of the androgen receptor gene ( AR), no single gene is altered in more than half of tumors. Structural genomic rearrangements are common, including ERG fusions, copy gains involving the MYC locus, and copy losses containing PTEN. Overall, instead of being associated with a single dominant driver event, prostate tumors display various combinations of modifications in oncogenes and tumor suppressors. This review takes a broad look at the recent advances in PCa research, including understanding the genetic alterations that drive the disease and how specific mutations can sensitize tumors to potential therapies. We begin with an overview of the genomic landscape of primary and metastatic PCa, enabled by recent large-scale sequencing efforts. Advances in three-dimensional cell culture techniques and mouse models for PCa are also discussed, and particular emphasis is placed on the benefits of patient-derived xenograft models. We also review research into understanding how ETS fusions (in particular, TMPRSS2-ERG) and SPOP mutations contribute to tumor initiation. Next, we examine the recent findings on the prevalence of germline DNA repair mutations in about 12% of patients with metastatic disease and their potential benefit from the use of poly(ADP-ribose) polymerase (PARP) inhibitors and immune modulation. Lastly, we discuss the recent increased prevalence of AR-negative tumors (neuroendocrine and double-negative) and the current state of immunotherapy in PCa. AR remains the primary clinical target for PCa therapies; however, it does not act alone, and better understanding of supporting mutations may help guide the development of novel therapeutic strategies.

Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

“…TMPRSS2 has a role in the entry of several coronaviruses, including SARS-CoV2, SARS-CoV, and MERS-CoV, as well as several types of influenza viruses (2,(8)(9)(10)(11)(12). TMPRSS2 also functions as an oncogene in prostate cancer, in which fusion events of TMPRSS2 and ERG2 occur (13). Therefore, TMPRSS2 is a promising target for drug development.…”

p53 mutant-type in human prostate cancer cells determines the sensitivity to phenethyl isothiocyanate induced growth inhibition

“…Recent studies on comprehensive characterization of the prostate cancer transcriptome and genome have revealed that p53 gene represents one of the most frequently mutated driver gene in primary prostate cancer [51] and mutations in p53 gene also occur at remarkably high frequency in metastatic tumors and metastatic castrationresistant prostate cancer (mCRPC) [52][53][54]. Mutations in the p53 gene occur at different stages of prostate tumorigenesis from early stage prostate cancer to its invasive or metastatic tumors or mCRPC, suggesting that p53 mutant is a potential target for therapeutic interventions in this disease.…”

Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers

“…Correlates of Oncogenic Signaling. Genomic studies of prostate cancer have identified driver alterations associated with disease progression (39). We sought to define how the variable cassette exons we identified and the biological processes they participate in might relate to these oncogenic signals.…”