A Fluorescence In situ Hybridization Screen for E26 Transformation–Specific Aberrations: Identification of DDX5-ETV4 Fusion Protein in Prostate Cancer
Journal - Cancer Research
Recurrent gene fusions involving E26 transformation–specific(ETS) transcription factors ERG, ETV1, ETV4, or ETV5 have beenidentified in 40% to 70% of prostate cancers. Here, we useda comprehensive fluorescence in situ hybridization (FISH) splitprobe strategy interrogating all 27 ETS family members and theirfive known 5' fusion partners in a cohort of 110 clinicallylocalized prostate cancer patients. Gene rearrangements wereonly identified in ETS genes that were previously implicatedin prostate cancer gene fusions including ERG, ETV1, and ETV4(43%, 5%, and 5%, respectively), suggesting that a substantialfraction of prostate cancers (estimated at 30–60%) cannotbe attributed to an ETS gene fusion. Among the known 5' genefusion partners, TMPRSS2 was rearranged in 47% of cases followedby SLC45A3, HNRPA2B1, and C15ORF21 in 2%, 1%, and 1% of cases,respectively. Based on this comprehensive FISH screen, we havemade four noteworthy observations. First, by screening the entireETS transcription factor family for rearrangements, we foundthat a large fraction of prostate cancers (44%) cannot be ascribedto an ETS gene fusion, an observation which will stimulate researchinto identifying recurrent non-ETS aberrations in prostate cancers.Second, we identified SLC45A3 as a novel 5' fusion partner ofERG; previously, TMPRSS2 was the only described 5' partner ofERG. Third, we identified two prostate-specific, androgen-inducedgenes, FLJ35294 and CANT1, as 5' partners to ETV1 and ETV4.Fourth, we identified a ubiquitously expressed, androgen-insensitivegene, DDX5, fused in frame with ETV4, leading to the expressionof a DDX5-ETV4 fusion protein. [Cancer Res 2008;68(18):7629–37]
|Keywords : ||gene fusion • prostate cancer • ETS • DDX5 • ETV4 • fusion protein|
Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer
Journal - Science
Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferasethat contributes to the epigenetic silencing of target genesand regulates the survival and metastasis of cancer cells. EZH2is overexpressed in aggressive solid tumors by mechanisms thatremain unclear. Here we show that the expression and functionof EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101).Analysis of human prostate tumors revealed that miR-101 expressiondecreases during cancer progression, paralleling an increasein EZH2 expression. One or both of the two genomic loci encodingmiR-101 were somatically lost in 37.5% of clinically localizedprostate cancer cells (6 of 16) and 66.7% of metastatic diseasecells (22 of 33). We propose that the genomic loss of miR-101in cancer leads to overexpression of EZH2 and concomitant dysregulationof epigenetic pathways, resulting in cancer progression.* These authors contributed equally to this work.