A rare variant in EZH2 is associated with prostate cancer risk.

Autor: Raspin K; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia., FitzGerald LM; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia., Marthick JR; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia., Field MA; Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Cairns, Queensland, Australia.; John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Malley RC; Hobart Pathology, Hobart, Tasmania, Australia.; Tasmanian School of Medicine, University of Tasmania, Hobart, Tasmania, Australia., Banks A; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia., Donovan S; Hobart Pathology, Hobart, Tasmania, Australia., Thomson RJ; Centre for Research in Mathematics and Data Science, Western Sydney University, Sydney, New South Wales, Australia., Foley GR; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia., Stanford JL; Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Dickinson JL; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2021 Sep 01; Vol. 149 (5), pp. 1089-1099. Date of Electronic Publication: 2021 Apr 12.
DOI: 10.1002/ijc.33584
Abstrakt: 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.
(© 2021 Union for International Cancer Control.)
Databáze: MEDLINE
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