ORCID Profile
0000-0001-8463-6820
Current Organisations
Menzies Research Institute Tasmania
,
University of Tasmania
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Publisher: Wiley
Date: 12-04-2021
DOI: 10.1002/IJC.33584
Abstract: Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole‐genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G A), was identified as segregating with disease in all but two in iduals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551 odds ratio [OR] = 3.55, P = 1.20 × 10 −5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild‐type cases. Although no allele‐dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild‐type s les. The gene expression signature comprised known downstream targets of EZH2 and included the top‐ranked genes, DUSP1 , FOS , JUNB and EGR1 , which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Wiley
Date: 07-01-2022
DOI: 10.1002/PROS.24300
Abstract: 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 ersity 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 s les, 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.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1038/S41598-017-18217-W
Abstract: The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour s les from variant and wild-type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers.
Publisher: Wiley
Date: 23-12-2022
DOI: 10.1002/GCC.23117
Abstract: 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 lification 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 lification 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 lified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 lification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly lified 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.
Publisher: Unpublished
Date: 2015
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2022
DOI: 10.1101/2022.04.27.22274348
Abstract: Family history is amongst the strongest risk factors for interstitial lung disease (ILD), with emerging evidence for a shared genetic aetiology across ILD subtypes. Recruited families comprised at least two first-degree relatives who had been previously diagnosed with an ILD. All living cases and available unaffected first-degree relatives underwent a clinical examination for evidence of ILD. Preclinical ILD was diagnosed in 47.7% of first-degree relatives who had previously self-reported as unaffected. This study highlights the strong genetic predisposition in family members of ILD cases, and supports the call for routine screening of in iduals with a family history of ILD.
No related grants have been discovered for Kelsie Raspin.