A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer.
Recurrent gene fusions involving E26 transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in 40% to 70% of prostate cancers. Here, we used a comprehensive fluorescence in situ hybridization (FISH) split probe strategy interrogating all 27 ETS family members and their five known 5' fusion partners in a cohort of 110 clinically localized prostate cancer patients. Gene rearrangements were only identified in ETS genes that were previously implicated in prostate cancer gene fusions including ERG, ETV1, and ETV4 (43%, 5%, and 5%, respectively), suggesting that a substantial fraction of prostate cancers (estimated at 30-60%) cannot be attributed to an ETS gene fusion. Among the known 5' gene fusion partners, TMPRSS2 was rearranged in 47% of cases followed by SLC45A3, HNRPA2B1, and C15ORF21 in 2%, 1%, and 1% of cases, respectively. Based on this comprehensive FISH screen, we have made four noteworthy observations. First, by screening the entire ETS transcription factor family for rearrangements, we found that a large fraction of prostate cancers (44%) cannot be ascribed to an ETS gene fusion, an observation which will stimulate research into identifying recurrent non-ETS aberrations in prostate cancers. Second, we identified SLC45A3 as a novel 5' fusion partner of ERG; previously, TMPRSS2 was the only described 5' partner of ERG. Third, we identified two prostate-specific, androgen-induced genes, FLJ35294 and CANT1, as 5' partners to ETV1 and ETV4. Fourth, we identified a ubiquitously expressed, androgen-insensitive gene, DDX5, fused in frame with ETV4, leading to the expression of a DDX5-ETV4 fusion protein.
Han
Bo
B
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Mehra
Rohit
R
Dhanasekaran
Saravana M
SM
Yu
Jindan
J
Menon
Anjana
A
Lonigro
Robert J
RJ
Wang
Xiaosong
X
Gong
Yusong
Y
Wang
Lei
L
Shankar
Sunita
S
Laxman
Bharathi
B
Shah
Rajal B
RB
Varambally
Sooryanarayana
S
Palanisamy
Nallasivam
N
Tomlins
Scott A
SA
Kumar-Sinha
Chandan
C
Chinnaiyan
Arul M
AM
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000235:genetics
D017500:Adenovirus E1A Proteins; C079853:ETV4 protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases
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