Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses id...

Full description

Saved in:

Bibliographic Details
Published in	Cell Vol. 179; no. 4; pp. 964 - 983.e31
Main Authors	Pan, Jianbo, Hu, Yingwei, Krek, Azra, Li, Yize, Chen, Lin S., Vasaikar, Suhas, Wu, Yige, Chowdhury, Shrabanti, Wyczalkowski, Matthew A., Kong, Andy, Sethuraman, Sunantha, Avtonomov, Dmitry M., Colaprico, Antonio, Cao, Song, Cho, Kyung-Cho, Kalayci, Selim, Ma, Shiyong, Ruggles, Kelly, Kawaler, Emily, Wen, Bo, Chen, Feng, Edwards, Nathan, Pierorazio, Phillip M., Pavlovich, Christian P., Brominski, Gabriel, Hsieh, James J., Lubinski, Jan, Wiznerowicz, Maciej, Kinsinger, Christopher R., Thiagarajan, Mathangi, Mesri, Mehdi, Hiltke, Tara, Ding, Li, Zhang, Zhen, Omenn, Gilbert S., Cieslik, Marcin, Nesvizhskii, Alexey I., Zhang, Hui, Hashimi, Abdul Samad, Charamut, Alyssa, Druker, Brian J., Tognon, Cristina, Mani, D.R., Rohrer, Daniel C., Tansil, Darlene, Chesla, David, Heiman, David, Wheeler, David, Chan, Doug, Demir, Emek, Wilson, George D., Liu, Hongwei, Zhou, Hua, Day, Jacob, Suh, James, Whiteaker, Jeffrey R., Eschbacher, Jennifer, Chen, Jin, Ketchum, Karen A., Rodland, Karin D., Krug, Karsten, Holloway, Kimberly, Sokoll, Lori J., Cornwell, MacIntosh, Loriaux, Marc, Anderson, Matthew, Ellis, Matthew J., Dyer, Maureen, Burke, Meghan C., Borucki, Melissa, Gillette, Michael A., Birrer, Michael J., Smith, Michael, Khan, Munziba, Roche, Nancy, Edwards, Nathan J., Vatanian, Negin, Tignor, Nicole, Piehowski, Paul, McGarvey, Peter B., Hariharan, Pushpa, Gao, Qingsong, Thangudu, Ratna R., Montgomery, Rebecca, Bremner, Ross, Liu, Ruiyang, Hong, Runyu, Payne, Samuel H., Patel, Shalin, Satpathy, Shankha, Davies, Sherri R., Patil, Snehal, Carter, Sonya, Gabriel, Stacey, Thomas, Stefani N., Carr, Steven A., Skelly, Tara, Borate, Uma, Maruvka, Yosef, Li, Zhi
Format	Journal Article
Language	English
Published	United States Elsevier Inc 31.10.2019
Subjects	Adult Aged Aged, 80 and over Biomarkers, Tumor - genetics Biomarkers, Tumor - immunology Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - immunology Carcinoma, Renal Cell - pathology ccRCC chromosomal translocation CPTAC Disease-Free Survival drug targets Exome - genetics Exome Sequencing Female Gene Expression Regulation, Neoplastic - genetics genetic instability Genome, Human - genetics genomics Humans immune infiltration Male metabolism Middle Aged Neoplasm Proteins - genetics Neoplasm Proteins - immunology Oxidative Phosphorylation phosphoproteomics Phosphorylation - genetics Proteogenomics proteomics renal carcinoma renal cell carcinoma Signal Transduction - genetics Transcriptome - genetics Transcriptome - immunology transcriptomics translation (genetics) tumor microenvironment Tumor Microenvironment - genetics Tumor Microenvironment - immunology phosphoproteomics ccRCC renal carcinoma proteomics immune infiltration drug targets tumor microenvironment CPTAC proteogenomics chromosomal translocation
Online Access	Get full text
ISSN	0092-8674 1097-4172 1097-4172
DOI	10.1016/j.cell.2019.10.007

Cover

More Information
Summary:	To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology. [Display omitted] •Integrated proteogenomic characterization in 103 ccRCC cases•Delineation of chromosomal translocation events leading to chromosome 3p loss•Tumor-specific proteomic/phosphoproteomic alterations unrevealed by mRNA analysis•Immune-based subtypes of ccRCC defined by mRNA, proteome, and phosphoproteome Comprehensive proteogenomic characterization in 103 treatment-naive clear cell renal cell carcinoma patient samples highlights tumor-specific alterations at the proteomic level that are unrevealed by transcriptomic profiling and proposes a revised subtyping scheme based on integrated omics analysis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, H.R., D.C., A.I.N., P.W., and H.Z.; Methodology, D.J.C. and L.C.; Software, F.P., J.P., X.S., Y.H., F.d.V.L., B.R., T.-S.M.L., H.-Y.C., W.M., C.H., A. Krek, Y.L., D.R., L.S.C., U.O., S.V., S.Y., S. Chowdhury, J.J., A. Kong, S.S., D.M.A., N.E., Z.Z., M.C., A.I.N., and P.W.; Validation, S.M.D., K.L.Q., and K.-C.C.; Formal Analysis, D.J.C., S.M.D., F.P., J.P., X.S., Y.H., B.R., T.-S.M.L., H.-Y.C., W.M., C.H., A. Krek, Y.L., D.R., L.S.C., U.O., S.V., Y.W., S.Y., S. Chowdhury, J.J., A. Kong, S.S., D.M.A., A. Colaprico, S. Cao, S. Kalayci, S.M., W.L., K.R., D.G., E.K., G.C.T., B.W., Y.Z., S. Keegan, K.L., F.C., N.E., A.I.N., P.W., and H.Z.; Investigation, D.J.C., L.C., M.S., K.-C.C., D.W.C., and H.Z.; Resources, Q.K.L., C.P.P., G.B., A.A., J.L., and M.T.; Data Curation, D.J.C., S.M.D., W.M., M.A.W., M.S., M.A., M.C., A.I.N., P.W., and H.Z.; Writing – Original Draft, D.J.C., A.I.N., P.W., and H.Z.; Writing – Review & Editing, all authors; Visualization, D.J.C., S.M.D., F.P., J.P., X.S., Y.H., B.R., T.-S.M.L., C.H., C.J.R., A. Krek, Y.L., D.R., U.O., S.V., M.A., A. Calinawan, Z.H.G., Y.Z., and M.C.; Supervision, D.J.C., S.M.D., C.J.R., P.M.P., X.S.C., C.P.P., A.A.H, G.B., J.H., A.A., T.O., J.L., M.W., W.M.L., J.Q., D.F., B.Z., L.D., E.S., A.M.C., Z.Z., G.S.O., D.W.C., A.I.N., P.W., and H.Z.; Project Administration, D.J.C., C.R.K., M.T., M.M., E.S.B., M.M., T.H., A.I.R., H.R., D.W.C., A.I.N., P.W., and H.Z.; Funding Acquisition, B.Z., L.D., D.F., E.S., A.M.C., Z.Z., D.W.C., A.I.N., P.W., and H.Z.
ISSN:	0092-8674 1097-4172 1097-4172
DOI:	10.1016/j.cell.2019.10.007