ABSTRACT
Inter- and intra-patient molecular heterogeneity of primary and metastatic prostate cancer (PCa) confers variable clinical outcome and poses a formidable challenge in disease management. High-throughput integrative genomics and functional approaches have untangled the complexity involved in this disease and revealed a spectrum of diverse aberrations prevalent in various molecular subtypes, including ETS fusion negative. Emerging evidence indicates that SPINK1 upregulation, mutations in epigenetic regulators or chromatin modifiers, and SPOP are associated with the ETS-fusion negative subtype. Additionally, patients with defects in a DNA-repair pathway respond to poly-(ADP-ribose)-polymerase (PARP) inhibition therapies. Furthermore, a new class of immunogenic subtype defined by CDK12 biallelic loss has also been identified in ETS-fusion-negative cases. This review focuses on the emerging molecular underpinnings driving key oncogenic aberrations and advancements in therapeutic strategies of this disease.
Subject(s)
Molecular Targeted Therapy/trends , Nuclear Proteins/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Prostatic Neoplasms , Repressor Proteins/genetics , Trypsin Inhibitor, Kazal Pancreatic/genetics , Cyclin-Dependent Kinases/genetics , DNA Repair , ETS Motif/genetics , Epigenetic Repression , Gene Expression Regulation, Neoplastic , Genomics , Humans , Loss of Heterozygosity , Male , Nuclear Proteins/metabolism , Phosphatidylethanolamine Binding Protein/pharmacology , Piperazines/therapeutic use , Poly (ADP-Ribose) Polymerase-1/drug effects , Precision Medicine/trends , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/therapy , Proteomics , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/metabolism , Pyrimidines/therapeutic use , Repressor Proteins/metabolism , Signal Transduction , Trypsin Inhibitor, Kazal Pancreatic/metabolismABSTRACT
Loss of B cell-specific transcription factors (TFs) and the resulting loss of B-cell phenotype of Hodgkin and Reed-Sternberg (HRS) cells is a hallmark of classical Hodgkin lymphoma (cHL). Here we have analysed two members of ETS domain containing TFs, ELF1 and ELF2, regarding (epi)genomic changes as well as gene and protein expression. We observed absence or lower levels of ELF1 protein in HRS cells of 31/35 (89%) cases compared to the bystander cells and significant (P < 0·01) downregulation of the gene on mRNA as well as protein level in cHL compared to non-cHL cell lines. However, no recurrent loss of ELF2 protein was observed. Moreover, ELF1 was targeted by heterozygous deletions combined with hypermethylation of the remaining allele(s) in 4/7 (57%) cell lines. Indeed, DNA hypermethylation (range 95-99%, mean 98%) detected in the vicinity of the ELF1 transcription start site was found in all 7/7 (100%) cHL cell lines. Similarly, 5/18 (28%) analysed primary biopsies carried heterozygous deletions of the gene. We demonstrate that expression of ELF1 is impaired in cHL through genetic and epigenetic alterations, and thus, it may represent an additional member of a TF network whose downregulation contributes to the loss of B-cell phenotype of HRS cells.