Molecular Subtypes of Prostate Cancer

Arora, Kaveri; Barbieri, Christopher E.

doi:10.1007/s11912-018-0707-9

Cited by 97 publications

(96 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Fusion involving TMPRSS2 and ERG accounts for 90% of the cases of fusion‐associated PrCa, and SLC45A3‐ERG has been reported as the second most‐frequent type of ERG rearrangement in this tumor . On the contrary, somatic mutations are, conversely less frequent than rearrangements and gene fusions, and with a lower prevalence than that found in other solid tumors …”

Section: Discussionmentioning

confidence: 85%

“…25,26 In addition, it has been reported that FOXA1 mutations in PrCa are mostly mutually exclusive with ETS-fusion and SPOP-mutant cases. 2 In this regard, FOXA1-mutant tumors from the TCGA cohort had similar molecular features compared to SPOP-mutant tumors, as gene expression, copy number, and methylation profiles. 1 On the other hand, IDH1 mutations are uncommon but characterize a new genomically distinct subtype of prostate cancer.…”

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

et al. 2019

View full text Add to dashboard Cite

Background ERG fusion‐related prostate cancer (PrCa) is the most prevalent oncogenic driver subclass. SPOP, FOXA1, and IDH1 mutations are other three main oncogenic driver subclasses in non–ETS‐fusion PrCa. ERG protein levels seem to be increased in SPOP‐mutated cases, and different studies reported that SPOP mutations and ERG fusions are mutually exclusive. The aim of this study has been to analyze the alterations in non–ETS‐oncogenic drivers in PrCa. Methods SPOP, FOXA1, and IDH mutations were investigated by polymerase chain reaction (PCR) and Sanger direct sequencing. ERG, SPOP, and TMPRSS2‐ERG messenger RNA expression was assessed by quantitative real‐time PCR from complementary DNA, and the presence of the fusion was also analyzed by nonquantitative PCR. The clinical pathological features were retrieved from the charts of the 111 patients included in the study (MARBiobanc, Barcelona, Spain). Results Loss of SPOP expression (25.2%) was associated with ERG overexpression (P = 0.0036). SPOP mutations were found in 5.4% cases, all with wild‐type (wt) ERG (P = 0.007). FOXA1 mutations were found in 8.2% cases, most of them ERG wt (P = 0.06). No IDH1 mutations were found. SPOP or FOXA1 mutations were found in 1.7% of ERG‐rearranged, and 34.2% of non–ERG‐rearranged cases (P < 0.0001). SPOP or FOXA1 alterations (mutations or expression loss) were significantly more common in GG5, while isolated ERG overexpression was more common in GG1 tumors (P = 0.042). SPOP‐or FOXA1‐mutated cases were associated with a shorter time to prostate‐specific antigen (PSA) recurrence in the univariate (P = 0.0009), and with the PSA recurrence risk in the multivariate (P = 0.023) analysis. Conclusions In conclusion, SPOP and FOXA1 mutations may have prognostic value in ERG wt tumors. Interestingly, in absence of SPOP mutations, downregulation of this gene is a feature of many ERG‐rearranged prostate tumors.

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 88%

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…AR is encoded by a ubiquitously expressed gene located in the X chromosome at Xq11-12 and is particularly important in prostate development and homeostasis (Lubahn et al 1988). When dysregulated, however, AR activity is central to the onset, development and progression to metastasis of prostate cancer (PCa), the most common cancer diagnosed in males worldwide (Matias et al 2000, Gottlieb et al 2004, Knudsen & Penning 2010, Arora & Barbieri 2018, Centenera et al 2018, Cioni et al 2018, Li et al 2018, Nevedomskaya et al 2018, Paschalis et al 2018. In addition, AR mutations are linked to disorders of male sexual differentiation and development termed androgen insensitivity syndromes (AIS) (Hughes et al 2012, Mongan et al 2015, Gibson et al 2018 and to the rare adult-onset hereditary neurodegenerative disorder known as spinal and bulbar muscular atrophy (SBMA or Kennedy's disease; OMIM #313200) (Spada et al 1991, Badders et al 2018, Cortes & La Spada 2018, Lieberman 2018, Pennuto & Rinaldi 2018.…”

Section: Genetic Bases Of Drug Resistance In Prostate Cancermentioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

View full text Add to dashboard Cite

Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

show abstract

“…Prostate cancers progress from hormone-responsive, localized disease to hormone-independent, metastatic disease accompanied by changes in gene expression and mutations that confer cellautonomous growth and therapeutic resistance (9). The study of disease progression from primary prostate adenocarcinoma (PrAd) to metastatic, castration-resistant prostate cancer (mCRPC) and treatment-related neuroendocrine prostate cancer (NEPC) has been aided by large-scale genomic and transcriptomic studies of patient samples representing each form of the disease (10)(11)(12)(13).…”

mentioning

confidence: 99%

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

Phillips

Pan

Tsai

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purposebuilt software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.alternative splicing | prostate cancer | Myc | rMATS | PEGASAS A lternative pre-mRNA splicing is a regulated process that governs exon choice and greatly diversifies the proteome. It is an essential process that contributes to development, tissue specification, and homeostasis and is often dysregulated in disease states (1). In cancer, this includes growth signaling, epithelial-tomesenchymal transition, resistance to apoptosis, and treatment resistance (2). In prostate cancer, our area of interest, the most notable splicing change is the emergence of the ligand-independent androgen receptor ARV7 isoform in response to hormone deprivation (3). Other examples include proangiogenic splice variants of VEGFA (4), tumorigenic variants of the transcription factors ERG and KLF6 (5, 6), and antiapoptotic splicing of BCL2L2 (7, 8). However, the intersection of upstream oncogenic signaling, pre-mRNA splicing, and the biological processes affected by those splicing events has not been defined at a global level.Prostate cancers progress from hormone-responsive, localized disease to hormone-independent, metastatic disease accompanied by changes in gene expression and mutations that confer cellautonomous growth and therapeutic resistance (9). The study of disease progression from primary prostate adenocarcinoma (PrAd) to metastatic, castration-resistant prostate cancer (mCRPC) and treatment-related neuroendocrine prostate cancer (NEPC) has been aided by large-scale genomic and transcriptomic studies of patient samples representing each form of the disease (10-13). E...

show abstract

Molecular Subtypes of Prostate Cancer

Cited by 97 publications

References 96 publications

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

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

Contact Info

Product

Resources

About