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Title: Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer

Abstract

Fusions between the transmembrane protease serine 2 (TMPRSS2) and ETS related gene (ERG) represent one of the most specific biomarkers that define a distinct molecular subtype of prostate cancer. The studies on TMPRSS2-ERG gene fusions have seldom been performed at the protein level, primarily due to the lack of high-quality antibodies or an antibody-independent method that is sufficiently sensitive for detecting the truncated ERG protein products resulting from TMPRSS2-ERG gene fusions and alternative splicing. Herein, we applied a recently developed PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) strategy for quantifying ERG protein in prostate cancer cell lines and tumors. The highly sensitive PRISM-SRM assays led to confident detection of 6 unique ERG peptides in either the TMPRSS2-ERG positive cell lines or tissues but not in the negative controls, indicating that ERG protein expression is highly correlated with TMPRSS2-ERG gene rearrangements. Significantly, our results demonstrated for the first time that at least two groups of ERG protein isoforms were simultaneously expressed at variable levels in TMPRSS2-ERG positive samples as evidenced by concomitant detection of two mutually exclusive peptides. Three peptides shared across almost all fusion protein products were determined to be the most abundant peptides, andmore » hence can be used as “signature” peptides for detecting ERG overexpression resulting from TMPRSS2-ERG gene fusion. These PRISM-SRM assays provide valuable tools for studying TMPRSS2-ERG gene fusion protein products, thus improving our understanding of the role of TMPRSS2-ERG gene fusion in the biology of prostate cancer.« less

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1176830
Report Number(s):
PNNL-SA-97917
43796; 400412000
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Oncology, 8(7):1169-1180
Country of Publication:
United States
Language:
English
Subject:
Environmental Molecular Sciences Laboratory

Citation Formats

He, Jintang, Sun, Xuefei, Shi, Tujin, Schepmoes, Athena A., Fillmore, Thomas L., Petyuk, Vladislav A., Xie, Fang, Zhao, Rui, Gritsenko, Marina A., Yang, Feng, Kitabayashi, Naoki, Chae, Sung Suk, Rubin, Mark, Siddiqui, Javed, Wei, John, Chinnaiyan, Arul M., Qian, Weijun, Smith, Richard D., Kagan, Jacob, Srivastava, Sudhir, Rodland, Karin D., Liu, Tao, and Camp, David G.. Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer. United States: N. p., 2014. Web. doi:10.1016/j.molonc.2014.02.004.
He, Jintang, Sun, Xuefei, Shi, Tujin, Schepmoes, Athena A., Fillmore, Thomas L., Petyuk, Vladislav A., Xie, Fang, Zhao, Rui, Gritsenko, Marina A., Yang, Feng, Kitabayashi, Naoki, Chae, Sung Suk, Rubin, Mark, Siddiqui, Javed, Wei, John, Chinnaiyan, Arul M., Qian, Weijun, Smith, Richard D., Kagan, Jacob, Srivastava, Sudhir, Rodland, Karin D., Liu, Tao, & Camp, David G.. Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer. United States. doi:10.1016/j.molonc.2014.02.004.
He, Jintang, Sun, Xuefei, Shi, Tujin, Schepmoes, Athena A., Fillmore, Thomas L., Petyuk, Vladislav A., Xie, Fang, Zhao, Rui, Gritsenko, Marina A., Yang, Feng, Kitabayashi, Naoki, Chae, Sung Suk, Rubin, Mark, Siddiqui, Javed, Wei, John, Chinnaiyan, Arul M., Qian, Weijun, Smith, Richard D., Kagan, Jacob, Srivastava, Sudhir, Rodland, Karin D., Liu, Tao, and Camp, David G.. Wed . "Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer". United States. doi:10.1016/j.molonc.2014.02.004.
@article{osti_1176830,
title = {Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer},
author = {He, Jintang and Sun, Xuefei and Shi, Tujin and Schepmoes, Athena A. and Fillmore, Thomas L. and Petyuk, Vladislav A. and Xie, Fang and Zhao, Rui and Gritsenko, Marina A. and Yang, Feng and Kitabayashi, Naoki and Chae, Sung Suk and Rubin, Mark and Siddiqui, Javed and Wei, John and Chinnaiyan, Arul M. and Qian, Weijun and Smith, Richard D. and Kagan, Jacob and Srivastava, Sudhir and Rodland, Karin D. and Liu, Tao and Camp, David G.},
abstractNote = {Fusions between the transmembrane protease serine 2 (TMPRSS2) and ETS related gene (ERG) represent one of the most specific biomarkers that define a distinct molecular subtype of prostate cancer. The studies on TMPRSS2-ERG gene fusions have seldom been performed at the protein level, primarily due to the lack of high-quality antibodies or an antibody-independent method that is sufficiently sensitive for detecting the truncated ERG protein products resulting from TMPRSS2-ERG gene fusions and alternative splicing. Herein, we applied a recently developed PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) strategy for quantifying ERG protein in prostate cancer cell lines and tumors. The highly sensitive PRISM-SRM assays led to confident detection of 6 unique ERG peptides in either the TMPRSS2-ERG positive cell lines or tissues but not in the negative controls, indicating that ERG protein expression is highly correlated with TMPRSS2-ERG gene rearrangements. Significantly, our results demonstrated for the first time that at least two groups of ERG protein isoforms were simultaneously expressed at variable levels in TMPRSS2-ERG positive samples as evidenced by concomitant detection of two mutually exclusive peptides. Three peptides shared across almost all fusion protein products were determined to be the most abundant peptides, and hence can be used as “signature” peptides for detecting ERG overexpression resulting from TMPRSS2-ERG gene fusion. These PRISM-SRM assays provide valuable tools for studying TMPRSS2-ERG gene fusion protein products, thus improving our understanding of the role of TMPRSS2-ERG gene fusion in the biology of prostate cancer.},
doi = {10.1016/j.molonc.2014.02.004},
journal = {Molecular Oncology, 8(7):1169-1180},
number = ,
volume = ,
place = {United States},
year = {Wed Oct 01 00:00:00 EDT 2014},
month = {Wed Oct 01 00:00:00 EDT 2014}
}