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A rare variant in EZH2 is associated with prostate cancer risk

Citation

Raspin, K and Fitzgerald, LM and Marthick, JR and Field, MA and Malley, RC and Banks, A and Donovan, S and Thomson, RJ and Foley, GR and Stanford, JL and Dickinson, JL, A rare variant in EZH2 is associated with prostate cancer risk, International Journal of Cancer pp. 1-11. ISSN 0020-7136 (2021) [Refereed Article]


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DOI: 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 individuals 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 samples. 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.

Item Details

Item Type:Refereed Article
Keywords:genetic susceptibility, prostate cancer, rare genetic variants, transcriptome analysis
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Raspin, K (Dr Kelsie Raspin)
UTAS Author:Fitzgerald, LM (Dr Liesel Fitzgerald)
UTAS Author:Marthick, JR (Mr James Marthick)
UTAS Author:Malley, RC (Dr Roslyn Malley)
UTAS Author:Banks, A (Mrs Annette Banks)
UTAS Author:Foley, GR (Miss Georgea Foley)
UTAS Author:Dickinson, JL (Professor Joanne Dickinson)
ID Code:144302
Year Published:2021
Web of Science® Times Cited:1
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-05-11
Last Modified:2021-05-11
Downloads:0

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