Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer.
Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease.
Mehra
Rohit
R
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Tomlins
Scott A
SA
Yu
Jianjun
J
Cao
Xuhong
X
Wang
Lei
L
Menon
Anjana
A
Rubin
Mark A
MA
Pienta
Kenneth J
KJ
Shah
Rajal B
RB
Chinnaiyan
Arul M
AM
D000728:Androgens / Q000378:metabolism*; D002869:Chromosome Aberrations; D015331:Cohort Studies; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
D000728:Androgens; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human