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

Authors:
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Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1389088
Grant/Contract Number:
AC05-76RL01830
Resource Type:
Journal Article: Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 166; Journal Issue: 3; Related Information: CHORUS Timestamp: 2017-09-09 08:20:43; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English

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., Rodland, Karin D., Carr, Steven A., Gillette, Michael A., Klauser, Karl R., Kuhn, Eric, Mani, D. R., Mertins, Philipp, Ketchum, Karen A., Thangudu, Ratna, Cai, Shuang, Oberti, Mauricio, Paulovich, Amanda G., Whiteaker, Jeffrey R., Edwards, Nathan J., McGarvey, Peter B., Madhavan, Subha, Wang, Pei, Chan, Daniel W., Pandey, Akhilesh, Shih, Ie-Ming, Zhang, Hui, Zhang, Zhen, Zhu, Heng, Cope, Leslie, Whiteley, Gordon A., Skates, Steven J., White, Forest M., Levine, Douglas A., Boja, Emily S., Kinsinger, Christopher R., Hiltke, Tara, Mesri, Mehdi, Rivers, Robert C., Rodriguez, Henry, Shaw, Kenna M., Stein, Stephen E., Fenyo, David, Liu, Tao, McDermott, Jason E., Payne, Samuel H., Rodland, Karin D., Smith, Richard D., Rudnick, Paul, Snyder, Michael, Zhao, Yingming, Chen, Xian, Ransohoff, David F., Hoofnagle, Andrew N., Liebler, Daniel C., Sanders, Melinda E., Shi, Zhiao, Slebos, Robbert J. C., Tabb, David L., Zhang, Bing, Zimmerman, Lisa J., Wang, Yue, Davies, Sherri R., Ding, Li, Ellis, Matthew J. C., and Townsend, R. Reid. 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., Carr, Steven A., Gillette, Michael A., Klauser, Karl R., Kuhn, Eric, Mani, D. R., Mertins, Philipp, Ketchum, Karen A., Thangudu, Ratna, Cai, Shuang, Oberti, Mauricio, Paulovich, Amanda G., Whiteaker, Jeffrey R., Edwards, Nathan J., McGarvey, Peter B., Madhavan, Subha, Wang, Pei, Chan, Daniel W., Pandey, Akhilesh, Shih, Ie-Ming, Zhang, Hui, Zhang, Zhen, Zhu, Heng, Cope, Leslie, Whiteley, Gordon A., Skates, Steven J., White, Forest M., Levine, Douglas A., Boja, Emily S., Kinsinger, Christopher R., Hiltke, Tara, Mesri, Mehdi, Rivers, Robert C., Rodriguez, Henry, Shaw, Kenna M., Stein, Stephen E., Fenyo, David, Liu, Tao, McDermott, Jason E., Payne, Samuel H., Rodland, Karin D., Smith, Richard D., Rudnick, Paul, Snyder, Michael, Zhao, Yingming, Chen, Xian, Ransohoff, David F., Hoofnagle, Andrew N., Liebler, Daniel C., Sanders, Melinda E., Shi, Zhiao, Slebos, Robbert J. C., Tabb, David L., Zhang, Bing, Zimmerman, Lisa J., Wang, Yue, Davies, Sherri R., Ding, Li, Ellis, Matthew J. C., & Townsend, R. Reid. 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., Rodland, Karin D., Carr, Steven A., Gillette, Michael A., Klauser, Karl R., Kuhn, Eric, Mani, D. R., Mertins, Philipp, Ketchum, Karen A., Thangudu, Ratna, Cai, Shuang, Oberti, Mauricio, Paulovich, Amanda G., Whiteaker, Jeffrey R., Edwards, Nathan J., McGarvey, Peter B., Madhavan, Subha, Wang, Pei, Chan, Daniel W., Pandey, Akhilesh, Shih, Ie-Ming, Zhang, Hui, Zhang, Zhen, Zhu, Heng, Cope, Leslie, Whiteley, Gordon A., Skates, Steven J., White, Forest M., Levine, Douglas A., Boja, Emily S., Kinsinger, Christopher R., Hiltke, Tara, Mesri, Mehdi, Rivers, Robert C., Rodriguez, Henry, Shaw, Kenna M., Stein, Stephen E., Fenyo, David, Liu, Tao, McDermott, Jason E., Payne, Samuel H., Rodland, Karin D., Smith, Richard D., Rudnick, Paul, Snyder, Michael, Zhao, Yingming, Chen, Xian, Ransohoff, David F., Hoofnagle, Andrew N., Liebler, Daniel C., Sanders, Melinda E., Shi, Zhiao, Slebos, Robbert J. C., Tabb, David L., Zhang, Bing, Zimmerman, Lisa J., Wang, Yue, Davies, Sherri R., Ding, Li, Ellis, Matthew J. C., and Townsend, R. Reid. Fri . "Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer". United States. doi:10.1016/j.cell.2016.05.069.
@article{osti_1389088,
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. and Carr, Steven A. and Gillette, Michael A. and Klauser, Karl R. and Kuhn, Eric and Mani, D. R. and Mertins, Philipp and Ketchum, Karen A. and Thangudu, Ratna and Cai, Shuang and Oberti, Mauricio and Paulovich, Amanda G. and Whiteaker, Jeffrey R. and Edwards, Nathan J. and McGarvey, Peter B. and Madhavan, Subha and Wang, Pei and Chan, Daniel W. and Pandey, Akhilesh and Shih, Ie-Ming and Zhang, Hui and Zhang, Zhen and Zhu, Heng and Cope, Leslie and Whiteley, Gordon A. and Skates, Steven J. and White, Forest M. and Levine, Douglas A. and Boja, Emily S. and Kinsinger, Christopher R. and Hiltke, Tara and Mesri, Mehdi and Rivers, Robert C. and Rodriguez, Henry and Shaw, Kenna M. and Stein, Stephen E. and Fenyo, David and Liu, Tao and McDermott, Jason E. and Payne, Samuel H. and Rodland, Karin D. and Smith, Richard D. and Rudnick, Paul and Snyder, Michael and Zhao, Yingming and Chen, Xian and Ransohoff, David F. and Hoofnagle, Andrew N. and Liebler, Daniel C. and Sanders, Melinda E. and Shi, Zhiao and Slebos, Robbert J. C. and Tabb, David L. and Zhang, Bing and Zimmerman, Lisa J. and Wang, Yue and Davies, Sherri R. and Ding, Li and Ellis, Matthew J. C. and Townsend, R. Reid},
abstractNote = {},
doi = {10.1016/j.cell.2016.05.069},
journal = {Cell},
number = 3,
volume = 166,
place = {United States},
year = {Fri Jul 01 00:00:00 EDT 2016},
month = {Fri Jul 01 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.cell.2016.05.069

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Cited by: 82works
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  • 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,more » 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.« less
  • We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the proteinmore » level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.« less
  • Here, mass spectrometry (MS) based targeted proteomic methods such as selected reaction monitoring (SRM) are becoming the method of choice for preclinical verification of candidate protein biomarkers. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute has investigated the standardization and analytical validation of the SRM assays and demonstrated robust analytical performance on different instruments across different laboratories. An Assay Portal has also been established by CPTAC to provide the research community a resource consisting of large set of targeted MS-based assays, and a depository to share assays publicly, providing that assays meet the guidelines proposed bymore » CPTAC. Herein, we report 98 SRM assays covering 70 candidate protein biomarkers previously reported as associated with ovarian cancer that have been thoroughly characterized according to the CPTAC Assay Characterization Guidance Document. The experiments, methods and results for characterizing these SRM assays for their MS response, repeatability, selectivity, stability, and reproducible detection of endogenous analytes are described in detail.« less
  • HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 andmore » OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression. - Highlights: • HOTAIR overexpression correlates with an aggressive tumour phenotype and a poor prognosis in SOC. • HOTAIR promotes SOC cell proliferation both in vitro and in vivo. • The proliferative role of HOTAIR is associated with regulation of the cell cycle and apoptosis.« less
  • The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis. Here, we observed that MUS81 was over-expressed in SOC tissues at both transcript and protein levels, andmore » the expression level of MUS81 protein in ovarian cancer cell lines was also higher than that in human normal ovarian surface epithelial cell line (HOSEpiC). We also found that down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression. Moreover, inhibition of MUS81 expression induced cellular senescence and enhanced the antitumor effect of cisplatin. Down-regulation of MUS81 expression could suppress the growth and development of SOC. These results indicate that MUS81 might play important roles in the progression of SOC and influence the antitumor effect of cisplatin. - Highlights: • MUS81 was overexpression in serous ovarian cancer (SOC). • Meanwhile down-regulation of inhibited cell proliferation and influenced cell cycle progression. • Inhibition of MUS81 induced cell cellular senescence and enhanced the antitumor effect of cisplatin. • Down-regulation of MUS81 expression could suppress the growth and development of SOC.« less