TY - JOUR
T1 - Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness
AU - Clinical Proteomic Tumor Analysis Consortium
AU - Li, Yize
AU - Lih, Tung Shing M.
AU - Dhanasekaran, Saravana M.
AU - Mannan, Rahul
AU - Chen, Lijun
AU - Cieslik, Marcin
AU - Wu, Yige
AU - Lu, Rita Jiu Hsien
AU - Clark, David J.
AU - Kołodziejczak, Iga
AU - Hong, Runyu
AU - Chen, Siqi
AU - Zhao, Yanyan
AU - Chugh, Seema
AU - Caravan, Wagma
AU - Naser Al Deen, Nataly
AU - Hosseini, Noshad
AU - Newton, Chelsea J.
AU - Krug, Karsten
AU - Xu, Yuanwei
AU - Cho, Kyung Cho
AU - Hu, Yingwei
AU - Zhang, Yuping
AU - Kumar-Sinha, Chandan
AU - Ma, Weiping
AU - Calinawan, Anna
AU - Wyczalkowski, Matthew A.
AU - Wendl, Michael C.
AU - Wang, Yuefan
AU - Guo, Shenghao
AU - Zhang, Cissy
AU - Le, Anne
AU - Dagar, Aniket
AU - Hopkins, Alex
AU - Cho, Hanbyul
AU - Leprevost, Felipe da Veiga
AU - Jing, Xiaojun
AU - Teo, Guo Ci
AU - Liu, Wenke
AU - Reimers, Melissa A.
AU - Pachynski, Russell
AU - Lazar, Alexander J.
AU - Chinnaiyan, Arul M.
AU - Van Tine, Brian A.
AU - Zhang, Bing
AU - Rodland, Karin D.
AU - Getz, Gad
AU - Mani, D. R.
AU - Wang, Pei
AU - Chen, Feng
AU - Hostetter, Galen
AU - Thiagarajan, Mathangi
AU - Linehan, W. Marston
AU - Fenyö, David
AU - Jewell, Scott D.
AU - Omenn, Gilbert S.
AU - Mehra, Rohit
AU - Wiznerowicz, Maciej
AU - Robles, Ana I.
AU - Mesri, Mehdi
AU - Hiltke, Tara
AU - An, Eunkyung
AU - Rodriguez, Henry
AU - Chan, Daniel W.
AU - Ricketts, Christopher J.
AU - Nesvizhskii, Alexey I.
AU - Zhang, Hui
AU - Ding, Li
AU - Francis, Alicia
AU - Paulovich, Amanda G.
AU - Antczak, Andrzej
AU - Green, Anthony
AU - Colaprico, Antonio
AU - Hakimi, Ari
AU - Pruetz, Barb
AU - Hindenach, Barbara
AU - Yadav, Birendra Kumar
AU - Reva, Boris
AU - Fevrier-Sullivan, Brenda
AU - Druker, Brian J.
AU - Szczylik, Cezary
AU - Goldthwaite, Charles A.
AU - Birger, Chet
AU - Jones, Corbin D.
AU - Rohrer, Daniel C.
AU - Tansil, Darlene
AU - Chesla, David
AU - Heiman, David
AU - Duffy, Elizabeth
AU - Schadt, Eri E.
AU - Petralia, Francesca
AU - Bromiński, Gabriel
AU - Quiroga-Garza, Gabriela M.
AU - Wilson, George D.
AU - Li, Ginny Xiaohe
AU - Zhao, Grace
AU - Hsiao, Yi
AU - Hsieh, James
AU - Lubiński, Jan
AU - Bavarva, Jasmin
AU - Huang, Jasmine
AU - Hafron, Jason
AU - Eschbacher, Jennifer
AU - Hon, Jennifer
AU - Francis, Jesse
AU - Freymann, John
AU - Vo, Josh
AU - Wang, Joshua
AU - Kirby, Justin
AU - Zaalishvili, Kakhaber
AU - Ketchum, Karen A.
AU - Hoadley, Katherine A.
AU - Um, Ki Sung
AU - Qi, Liqun
AU - Domagalski, Marcin J.
AU - Tobin, Matt
AU - Dyer, Maureen
AU - Anurag, Meenakshi
AU - Borucki, Melissa
AU - Gillette, Michael A.
AU - Birrer, Michael J.
AU - Ittmann, Michael M.
AU - Roehrl, Michael H.
AU - Schnaubelt, Michael
AU - Smith, Michael
AU - Fam, Mina
AU - Roche, Nancy
AU - Vatanian, Negin
AU - Maunganidze, Nicollette
AU - Potapova, Olga
AU - Paklina, Oxana V.
AU - VanderKolk, Pamela
AU - Castro, Patricia
AU - Kurzawa, Paweł
AU - Hariharan, Pushpa
AU - Li, Qin
AU - Li, Qing Kay
AU - Dhir, Rajiv
AU - Thangudu, Ratna R.
AU - Montgomery, Rebecca
AU - Smith, Richard D.
AU - Mareedu, Sailaja
AU - Payne, Samuel H.
AU - Cerda, Sandra
AU - Cottingham, Sandra
AU - Haynes, Sarah
AU - Satpathy, Shankha
AU - Richey, Shannon
AU - Singh, Shilpi
AU - Tsang, Shirley X.
AU - Cai, Shuang
AU - Cao, Song
AU - Gabriel, Stacey
AU - Carr, Steven A.
AU - Liu, Tao
AU - Bauer, Thomas
AU - Le, Toan
AU - Chen, Xi S.
AU - Zhang, Xu
AU - Shutack, Yvonne
AU - Zhang, Zhen
N1 - Funding Information:
This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Institutes of Health under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, U01CA214125, U24CA271114, U24CA271079, and U24CA271037. NCI U2CCA233303 to L.D. supported this work. Study conception & design, Y.L. S.M.D. D.W.C. C.J.R. A.I.N. H.Z. and L.D.; performed experiments or data collection, Y.L. L.C. D.J.C. C.J.N. Y.X. K.-C.C. N.N.A.D. Y.Z. W.C. A.L. R.M. X.J. S.C. G.C.T. M.T. A.I.N. H.Z. and L.D.; computational, multi-omic, & statistical analyses, Y.L. T.M.L. R.M. M.C. Y.W. R.J.-H.L. R.H. K.K. Y.H. Y.Z. N.H. W.M. A.C. M.A.W. Y.W. S.G. C.Z. A.D. A.H. H.C. F.D. W.L. A.I.N. H.Z. and L.D.; data interpretation & biological analysis, Y.L. T.M.L. S.M.D. R.M. M.C. Y.W. R.J.-H.L. D.J.C. R.H. S.C. K.K. I.K. A.C. B.A.V.T. B.Z. M.W. C.J.R. A.I.N. H.Z. and L.D.; writing – original drafts, Y.L. T.M.L. S.M.D. C.J.R. H.Z. and L.D.; writing – review & editing, Y.L. T.M.L. S.M.D. R.M. C.K.-S. M.C.W. M.A.R. R.P. A.J.L. F.C. B.A.V.T. B.Z. K.D.R. G.G. R.M. A.I.R. M.M. T.H. E.A. H.R. C.J.R. A.I.N. H.Z. and L.D.; supervision, Y.L. S.M.D. G.G. D.R.M. P.W. M.W. G.H. M.T. W.M.L. D.F. S.D.J. G.S.O. R.M. A.I.R. M.M. T.H. E.A. H.R. D.W.C. C.J.R. A.I.N. H.Z. and L.D.; administration, Y.L. A.I.R. M.M. T.H. E.A. H.R. D.W.C. A.I.N. H.Z. and L.D. The authors declare no competing interests.
Funding Information:
This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Institutes of Health under award numbers U24CA210955 , U24CA210985 , U24CA210986 , U24CA210954 , U24CA210967 , U24CA210972 , U24CA210979 , U24CA210993 , U01CA214114 , U01CA214116 , U01CA214125 , U24CA271114 , U24CA271079 , and U24CA271037 . NCI U2CCA233303 to L.D. supported this work.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/9
Y1 - 2023/1/9
N2 - 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.
AB - 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.
KW - CPTAC
KW - UCHL1
KW - clear cell renal cell carcinoma
KW - glycoproteomics
KW - histology
KW - metabolome
KW - phosphoproteomics
KW - proteogenomics
KW - single-nuclei RNA-seq
KW - tumor heterogeneity
UR - http://www.scopus.com/inward/record.url?scp=85146040487&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.12.001
DO - 10.1016/j.ccell.2022.12.001
M3 - Article
C2 - 36563681
AN - SCOPUS:85146040487
SN - 1535-6108
VL - 41
SP - 139-163.e17
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -