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Title: Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer

Abstract

Ovarian cancer remains the most lethal gynecological malignancy in the developed world, despite recent advances in genomic information and treatment. To better understand this disease, define an integrated proteogenomic landscape, and identify factors associated with homologous repair deficiency (HRD) and overall survival, we performed a comprehensive proteomic characterization of ovarian high-grade serous carcinomas (HGSC) previously characterized by The Cancer Genome Atlas (TCGA). We observed that messenger RNA transcript abundance did not reliably predict abundance for 10,030 proteins across 174 tumors. Clustering of tumors based on protein abundance identified five subtypes, two of which correlated robustly with mesenchymal and proliferative subtypes, while tumors characterized as immunoreactive or differentiated at the transcript level were intermixed at the protein level. At the genome level, HGSC is characterized by a complex landscape of somatic copy number alterations (CNA), which individually do not correlate significantly with survival. Correlation of CNAs with protein abundances identified loci with significant trans regulatory effects mapping to pathways associated with proliferation, cell motility/invasion, and immune regulation, three known hallmarks of cancer. Using the trans regulated proteins we also created models significantly correlated with patient survival by multivariate analysis. Integrating protein abundance with specific post-translational modification data identified subnetworks correlated withmore » HRD status; specifically, acetylation of Lys12 and Lys16 on histone H4 was associated with HRD status. Using quantitative phosphoproteomics data covering 4,420 proteins as reflective of pathway activity, we identified the PDGFR and VEGFR signaling pathways as significantly up-regulated in patients with short overall survival, independent of PDGFR and VEGFR protein levels, potentially informing the use of anti-angiogenic therapies. Components of the Rho/Rac/Cdc42 cell motility pathways were also significantly enriched for short survival. Overall, proteomics provided new insights into ovarian cancer not apparent from genomic analysis and enabling a deeper understanding of HGSC with the potential to inform targeted therapeutics.« 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:
1322516
Report Number(s):
PNNL-SA-107151
Journal ID: ISSN 0092-8674; 48135; 48666; 400412000
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cell; Journal Volume: 166; Journal Issue: 3
Country of Publication:
United States
Language:
English
Subject:
Environmental Molecular Sciences Laboratory

Citation Formats

Zhang, Hui, Liu, Tao, Zhang, Zhen, Payne, Samuel H., Zhang, Bai, McDermott, Jason E., Zhou, Jian-Ying, Petyuk, Vladislav A., Chen, Li, Ray, Debjit, Sun, Shisheng, Yang, Feng, Chen, Lijun, Wang, Jing, Shah, Punit, Cha, Seong Won, Aiyetan, Paul, Woo, Sunghee, Tian, Yuan, Gritsenko, Marina A., Clauss, Therese R., Choi, Caitlin, Monroe, Matthew E., Thomas, Stefani, Nie, Song, Wu, Chaochao, Moore, Ronald J., Yu, Kun-Hsing, Tabb, David L., Fenyö, David, Bafna, Vineet, Wang, Yue, Rodriguez, Henry, Boja, Emily S., Hiltke, Tara, Rivers, Robert C., Sokoll, Lori, Zhu, Heng, Shih, Ie-Ming, Cope, Leslie, Pandey, Akhilesh, Zhang, Bing, Snyder, Michael P., Levine, Douglas A., Smith, Richard D., Chan, Daniel W., and Rodland, Karin D. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer. United States: N. p., 2016. Web. doi:10.1016/j.cell.2016.05.069.
Zhang, Hui, Liu, Tao, Zhang, Zhen, Payne, Samuel H., Zhang, Bai, McDermott, Jason E., Zhou, Jian-Ying, Petyuk, Vladislav A., Chen, Li, Ray, Debjit, Sun, Shisheng, Yang, Feng, Chen, Lijun, Wang, Jing, Shah, Punit, Cha, Seong Won, Aiyetan, Paul, Woo, Sunghee, Tian, Yuan, Gritsenko, Marina A., Clauss, Therese R., Choi, Caitlin, Monroe, Matthew E., Thomas, Stefani, Nie, Song, Wu, Chaochao, Moore, Ronald J., Yu, Kun-Hsing, Tabb, David L., Fenyö, David, Bafna, Vineet, Wang, Yue, Rodriguez, Henry, Boja, Emily S., Hiltke, Tara, Rivers, Robert C., Sokoll, Lori, Zhu, Heng, Shih, Ie-Ming, Cope, Leslie, Pandey, Akhilesh, Zhang, Bing, Snyder, Michael P., Levine, Douglas A., Smith, Richard D., Chan, Daniel W., & Rodland, Karin D. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer. United States. doi:10.1016/j.cell.2016.05.069.
Zhang, Hui, Liu, Tao, Zhang, Zhen, Payne, Samuel H., Zhang, Bai, McDermott, Jason E., Zhou, Jian-Ying, Petyuk, Vladislav A., Chen, Li, Ray, Debjit, Sun, Shisheng, Yang, Feng, Chen, Lijun, Wang, Jing, Shah, Punit, Cha, Seong Won, Aiyetan, Paul, Woo, Sunghee, Tian, Yuan, Gritsenko, Marina A., Clauss, Therese R., Choi, Caitlin, Monroe, Matthew E., Thomas, Stefani, Nie, Song, Wu, Chaochao, Moore, Ronald J., Yu, Kun-Hsing, Tabb, David L., Fenyö, David, Bafna, Vineet, Wang, Yue, Rodriguez, Henry, Boja, Emily S., Hiltke, Tara, Rivers, Robert C., Sokoll, Lori, Zhu, Heng, Shih, Ie-Ming, Cope, Leslie, Pandey, Akhilesh, Zhang, Bing, Snyder, Michael P., Levine, Douglas A., Smith, Richard D., Chan, Daniel W., and Rodland, Karin D. 2016. "Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer". United States. doi:10.1016/j.cell.2016.05.069.
@article{osti_1322516,
title = {Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer},
author = {Zhang, Hui and Liu, Tao and Zhang, Zhen and Payne, Samuel H. and Zhang, Bai and McDermott, Jason E. and Zhou, Jian-Ying and Petyuk, Vladislav A. and Chen, Li and Ray, Debjit and Sun, Shisheng and Yang, Feng and Chen, Lijun and Wang, Jing and Shah, Punit and Cha, Seong Won and Aiyetan, Paul and Woo, Sunghee and Tian, Yuan and Gritsenko, Marina A. and Clauss, Therese R. and Choi, Caitlin and Monroe, Matthew E. and Thomas, Stefani and Nie, Song and Wu, Chaochao and Moore, Ronald J. and Yu, Kun-Hsing and Tabb, David L. and Fenyö, David and Bafna, Vineet and Wang, Yue and Rodriguez, Henry and Boja, Emily S. and Hiltke, Tara and Rivers, Robert C. and Sokoll, Lori and Zhu, Heng and Shih, Ie-Ming and Cope, Leslie and Pandey, Akhilesh and Zhang, Bing and Snyder, Michael P. and Levine, Douglas A. and Smith, Richard D. and Chan, Daniel W. and Rodland, Karin D.},
abstractNote = {Ovarian cancer remains the most lethal gynecological malignancy in the developed world, despite recent advances in genomic information and treatment. To better understand this disease, define an integrated proteogenomic landscape, and identify factors associated with homologous repair deficiency (HRD) and overall survival, we performed a comprehensive proteomic characterization of ovarian high-grade serous carcinomas (HGSC) previously characterized by The Cancer Genome Atlas (TCGA). We observed that messenger RNA transcript abundance did not reliably predict abundance for 10,030 proteins across 174 tumors. Clustering of tumors based on protein abundance identified five subtypes, two of which correlated robustly with mesenchymal and proliferative subtypes, while tumors characterized as immunoreactive or differentiated at the transcript level were intermixed at the protein level. At the genome level, HGSC is characterized by a complex landscape of somatic copy number alterations (CNA), which individually do not correlate significantly with survival. Correlation of CNAs with protein abundances identified loci with significant trans regulatory effects mapping to pathways associated with proliferation, cell motility/invasion, and immune regulation, three known hallmarks of cancer. Using the trans regulated proteins we also created models significantly correlated with patient survival by multivariate analysis. Integrating protein abundance with specific post-translational modification data identified subnetworks correlated with HRD status; specifically, acetylation of Lys12 and Lys16 on histone H4 was associated with HRD status. Using quantitative phosphoproteomics data covering 4,420 proteins as reflective of pathway activity, we identified the PDGFR and VEGFR signaling pathways as significantly up-regulated in patients with short overall survival, independent of PDGFR and VEGFR protein levels, potentially informing the use of anti-angiogenic therapies. Components of the Rho/Rac/Cdc42 cell motility pathways were also significantly enriched for short survival. Overall, proteomics provided new insights into ovarian cancer not apparent from genomic analysis and enabling a deeper understanding of HGSC with the potential to inform targeted therapeutics.},
doi = {10.1016/j.cell.2016.05.069},
journal = {Cell},
number = 3,
volume = 166,
place = {United States},
year = 2016,
month = 7
}
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