A rare variant in EZH2 is associated with prostate cancer risk

Raspin, Kelsie, FitzGerald, Liesel M., Marthick, James R., Field, Matt A., Malley, Roslyn C., Banks, Annette, Donovan, Shaun, Thomson, Russell J., Foley, Georgea R., Stanford, Janet L., and Dickinson, Joanne L. (2021) A rare variant in EZH2 is associated with prostate cancer risk. International Journal of Cancer, 149 (5). pp. 1089-1099.

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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 ID: 72410
Item Type: Article (Research - C1)
ISSN: 1097-0215
Keywords: prostate cancer, rare genetic variants, genetic susceptibility, transcriptome analysis
Copyright Information: This article is protected by copyright. All rights reserved.
Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC Grant/Award Number: FT120100623, NHMRC Grant/Award Number: APP5121190
Date Deposited: 15 Feb 2022 05:43
FoR Codes: 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 50%
31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310208 Translational and applied bioinformatics @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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