期刊
INTERNATIONAL JOURNAL OF CANCER
卷 149, 期 5, 页码 1089-1099出版社
WILEY
DOI: 10.1002/ijc.33584
关键词
genetic susceptibility; prostate cancer; rare genetic variants; transcriptome analysis
类别
资金
- Select Foundation Cancer Research Fellowship
- Australian Research Council Future Fellowship
- Australian Government Research Training Program Scholarship
- Cancer Council Tasmania Evelyn Pedersen Elite Research Scholarship
- Royal Hobart Hospital Research Foundation
- Cancer Council Tasmania/College of Health and Medicine Senior Research Fellowship
- NHMRC [APP5121190]
- Cancer Council Tasmania
- Cancer Australia
- Mazda Foundation
- Perpetual Trustees
- Max Bruce Trust
- Tasmanian Community Fund
A rare variant (rs78589034) was identified as significantly associated with increased prostate cancer risk, potentially affecting EZH2 function in prostate tissue. This provides evidence for the variant as a potential therapeutic target.
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 x 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据