Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

• Published in: Cancer cell Vol. 41; no. 1; pp. 139 - 163.e17
• Main Authors: Lih, Tung-Shing M., Mannan, Rahul, Cieslik, Marcin, Wu, Yige, Lu, Rita Jiu-Hsien, Clark, David J., Kołodziejczak, Iga, Hong, Runyu, Caravan, Wagma, Naser Al Deen, Nataly, Hosseini, Noshad, Krug, Karsten, Xu, Yuanwei, Wendl, Michael C., Zhang, Cissy, Cho, Hanbyul, Leprevost, Felipe da Veiga, Teo, Guo Ci, Reimers, Melissa A., Lazar, Alexander J., Chinnaiyan, Arul M., Van Tine, Brian A., Rodland, Karin D., Getz, Gad, Mani, D.R., Hostetter, Galen, Linehan, W. Marston, Jewell, Scott D., Omenn, Gilbert S., Wiznerowicz, Maciej, Robles, Ana I., Hiltke, Tara, An, Eunkyung, Rodriguez, Henry, Chan, Daniel W., Nesvizhskii, Alexey I., Zhang, Hui, Francis, Alicia, Paulovich, Amanda G., Antczak, Andrzej, Green, Anthony, Colaprico, Antonio, Pruetz, Barb, Yadav, Birendra Kumar, Reva, Boris, Fevrier-Sullivan, Brenda, Druker, Brian J., Goldthwaite, Charles A., Rohrer, Daniel C., Tansil, Darlene, Chesla, David, Duffy, Elizabeth, Schadt, Eri E., Bromiński, Gabriel, Wilson, George D., Hsieh, James, Lubiński, Jan, Bavarva, Jasmin, Huang, Jasmine, Hafron, Jason, Eschbacher, Jennifer, Hon, Jennifer, Francis, Jesse, Freymann, John, Wang, Joshua, Kirby, Justin, Zaalishvili, Kakhaber, Ketchum, Karen A., Um, Ki Sung, Domagalski, Marcin J., Tobin, Matt, Dyer, Maureen, Anurag, Meenakshi, Ittmann, Michael M., Roehrl, Michael H., Smith, Michael, Roche, Nancy, Maunganidze, Nicollette, Potapova, Olga, Castro, Patricia, Kurzawa, Paweł, Hariharan, Pushpa, Li, Qin, Montgomery, Rebecca, Smith, Richard D., Mareedu, Sailaja, Cerda, Sandra, Haynes, Sarah, Satpathy, Shankha, Richey, Shannon, Tsang, Shirley X., Cai, Shuang, Cao, Song, Gabriel, Stacey, Carr, Steven A., Liu, Tao, Bauer, Thomas, Le, Toan, Chen, Xi S., Zhang, Zhen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2023
• Subjects: Biomarkers, Tumor - genetics; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; clear cell renal cell carcinoma; CPTAC; glycoproteomics; histology; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; metabolome; phosphoproteomics; Prognosis; Proteogenomics; single-nuclei RNA-seq; Treatment Outcome; tumor heterogeneity; UCHL1; phosphoproteomics; glycoproteomics; UCHL1; clear cell renal cell carcinoma; histology; single-nuclei RNA-seq; CPTAC; proteogenomics; metabolome; tumor heterogeneity
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2022.12.001

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies. [Display omitted] •Integrated multi-omics and histopathology reveal intratumoral heterogeneity in ccRCCs•Signatures of aggressive sarcomatoid and rhabdoid histology are uncovered by snRNA-seq•High-grade ccRCCs have specific glycoproteomic, metabolomic, and methylation signatures•UCHL1 correlates with methylation, genome instability, BAP1 mutation, and poor survival Li et al. integrate histopathologic, proteogenomic, and metabolomic data from 305 tumor segments and reveal intratumoral heterogeneity in at least 90% of clear cell renal cell carcinomas, signatures for sarcomatoid and rhabdoid features, and prognostic value of UCHL1. This study molecularly stratifies aggressive histopathologic subtypes to inform effective treatment strategies.