Delineation of TMPRSS2-ERG splice variants in prostate cancer.
OBJECTIVE
The expression of the ETS-related gene (ERG) is low or undetectable in benign prostate epithelial cells. High prevalence of ERG overexpression in prostate cancer cells due to TMPRSS2-ERG fusions suggest for causal roles of ERG protein in the neoplastic process. TMPRSS2-ERG fusion junctions have been extensively studied in prostate cancer. However, virtually nothing is known about the nature of full-length transcripts and encoded proteins. This study focuses on qualitative and quantitative features of full-length TMPRSS2-ERG transcripts in prostate cancer.


METHODS
Full-length TMPRSS2-ERG transcripts were cloned and sequenced from a cDNA library generated from pooled RNA of six TMPRSS2-ERG fusion-positive prostate tumors. The encoded ERG proteins were analyzed in HEK293 cells. Copy numbers of TMPRSS2-ERG splice variants were determined by quantitative reverse transcription-PCR in laser capture microdissected prostate cancer cells.


RESULTS
Two types of TMPRSS2-ERG cDNAs were identified: type I, which encodes full-length prototypical ERG protein (ERG1, ERG2, ERG3), and type II, encoding truncated ERG proteins lacking the ETS domain (ERG8 and a new variant, TEPC). In microdissected prostate tumor cells from 122 patients, relative abundance of these variants was in the following order: ERG8 > TEPC > ERG 3 > ERG1/2 with combined overexpression rate of 62.3% in prostate cancer. Increased ratio of type I over type II splice forms showed a trend of correlation with less favorable pathology and outcome.


CONCLUSIONS
Qualitative and quantitative features of specific ERG splice variants defined here promise to enhance the utility of ERG as a biomarker and therapeutic target in prostate cancer.
Hu
Ying
Y
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland 20852, USA.
Dobi
Albert
A
Sreenath
Taduru
T
Cook
Christopher
C
Tadase
Atekelt Y
AY
Ravindranath
Lakshmi
L
Cullen
Jennifer
J
Furusato
Bungo
B
Chen
Yongmei
Y
Thangapazham
Rajesh L
RL
Mohamed
Ahmed
A
Sun
Chen
C
Sesterhenn
Isabell A
IA
McLeod
David G
DG
Petrovics
Gyorgy
G
Srivastava
Shiv
S
D017398:Alternative Splicing; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
D014408:Biomarkers, Tumor; D018076:DNA, Complementary; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human