A rare variant in <scp><i>EZH2</i></scp> is associated with prostate cancer risk

Raspin, Kelsie; FitzGerald, Liesel M.; Marthick, James R.; Field, Matthew A.; Malley, RC; Banks, Annette; Thomson, Russell; Foley, Georgea R.; Stanford, Janet L.; Dickinson, Joanne L.

doi:10.1002/ijc.33584

Cited by 10 publications

(5 citation statements)

References 56 publications

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“…The Tasmanian PrCa resource includes a rare collection of 73 Caucasian PrCa families from the founder population of Tasmania, as previously described 16,17 . This study focused on family PcTas9 (Figure ), in which 61 cases of PrCa have been identified through the Tasmanian Cancer Registry.…”

Section: Methodsmentioning

confidence: 99%

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition

et al. 2022

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There is strong interest in the characterisation of gene fusions and their use to enhance clinical practices in prostate cancer (PrCa). Significantly, ~50% of prostate tumours harbour a gene fusion. Inherited factors are thought to predispose to these events but, to date, only one study has investigated gene fusions in a familial context. Here, we examined the prevalence and diversity of gene fusions in 14 tumours from a single large PrCa family, PcTas9, using the TruSight® RNA Fusion Panel and Sanger sequencing validation. These fusions were then explored in The Cancer Genome Atlas (TCGA) PrCa data set (n = 494). Overall, 64.3% of PcTas9 tumours harboured a gene fusion, including known erythroblast transformation‐specific (ETS) fusions involving ERG and ETV1, and two novel gene fusions, C19orf48:ETV4 and RYBP:FOXP1. Although 3′ ETS genes were overexpressed in PcTas9 and TCGA tumour samples, 3′ fusion of FOXP1 did not appear to alter its expression. In addition, PcTas9 fusion carriers were more likely to have lower‐grade disease than noncarriers (p = 0.02). Likewise, TCGA tumours with high‐grade disease were less likely to harbour fusions (p = 0.03). Our study further implicates an inherited predisposition to PrCa gene fusion events, which are associated with less aggressive tumours. This knowledge could lead to clinical strategies to predict men at risk for fusion‐positive PrCa and, thus, identify patients who are more or less at risk of aggressive disease and/or responsive to particular therapies.

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Section: Methodsmentioning

confidence: 99%

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition

et al. 2022

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“…Tumor samples were sourced from two Australian studies, the Tasmanian Familial Prostate Cancer Cohort and the population‐based Tasmanian Prostate Cancer Case–Control Study , both of which have been described previously 7–10 . Familial PrCa is defined as families with two or more affected first‐degree relatives.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor samples were sourced from two Australian studies, the Tasmanian Familial Prostate Cancer Cohort and the population-based Tasmanian Prostate Cancer Case-Control Study, both of which have been described previously. [7][8][9][10] Familial PrCa is defined as families with two or more affected first-degree relatives. Archived prostate tissue pathology blocks from familial and sporadic PrCa cases were collected from local pathology laboratories.…”

Section: Australian Prostate Tumor Samplesmentioning

confidence: 99%

Identification of a novel recurrent EEF2 gene amplification in familial prostate tumors

Raspin

Marthick

Blizzard

et al. 2022

Genes Chromosomes & Cancer

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Recurrent tumor copy number variations (CNVs) in prostate cancer (PrCa) have predominantly been discovered in sporadic tumor cohorts. Here, we examined familial prostate tumors for novel CNVs as prior studies suggest these harbor distinct CNVs. Array comparative genomic hybridization of 12 tumors from an Australian PrCa family, PcTas9, highlighted multiple recurrent CNVs, including amplification of EEF2 (19p13.3) in 100% of tumors. The EEF2 CNV was examined in a further 26 familial and seven sporadic tumors from the Australian cohort and in 494 tumors unselected for family history from The Cancer Genome Atlas (TCGA). EEF2 overexpression was observed in seven PcTas9 tumors, in addition to seven other predominantly familial tumors (n total = 34%). EEF2 amplification was only observed in 1.4% of TCGA tumors, however 7.5% harbored an EEF2 deletion.Analysis of genes co-expressed with EEF2 revealed significant upregulation of two genes, ZNF74 and ADSL, and downregulation of PLSCR1 in both EEF2 amplified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 amplification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly amplified in familial tumors and deleted in unselected tumors. Our results provide further evidence that familial tumors harbor distinct CNVs, potentially due to an inherited predisposition, but also suggest that regardless of how EEF2 is dysregulated, a similar set of genes involved in key cancer pathways are impacted. Given the current lack of gene-based biomarkers and clinical targets in PrCa, further investigation of EEF2 is warranted.

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“…Thus, EZH2 inhibitors are potential candidates for CRPC therapies. Two EZH2 variants (rs78589034 90 and rs2302427 91 ) are associated with increased prostate cancer risk.…”

Section: Histone Methyltransferases/demethylases In Prostate Cancermentioning

confidence: 99%

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

Takahashi

Takada

2023

Asian Journal of Andrology

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Prostate cancer is one of the most common diseases in men worldwide. Surgery, radiation therapy, and hormonal therapy are effective treatments for early-stage prostate cancer. However, the development of castration-resistant prostate cancer has increased the mortality rate of prostate cancer. To develop novel drugs for castration-resistant prostate cancer, the molecular mechanisms of prostate cancer progression must be elucidated. Among the signaling pathways regulating prostate cancer development, recent studies have revealed the importance of noncanonical wingless-type MMTV integration site family (WNT) signaling pathways, mainly that involving WNT5A, in prostate cancer progression and metastasis; however, its role remains controversial. Moreover, chromatin remodelers such as the switch/sucrose nonfermentable (SWI/SNF) complex and chromodomain helicase DNA-binding proteins 1 also play important roles in prostate cancer progression through genome-wide gene expression changes. Here, we review the roles of noncanonical WNT signaling pathways, chromatin remodelers, and epigenetic enzymes in the development and progression of prostate cancer.

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A rare variant in EZH2 is associated with prostate cancer risk

Cited by 10 publications

References 56 publications

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition

Identification of a novel recurrent EEF2 gene amplification in familial prostate tumors

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

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