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Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade

We conducted integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients and identified molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis revealed six molecular subsets with distinct angiogenesis, immune, cell cycle, metabolism, and stromal programs. While sunitinib was effective in subsets with high angiogenesis, atezolizumab+bevacizumab improved clinical benefit in tumors with high T-effector and/or cell cycle transcription. Somatic mutations in PBRM1 and KDM5C associated with high angiogenesis and AMPK/Fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations were more prevalent in tumors with increased cell cycle and anabolic metabolism. Sarcomatoid tumors exhibited low prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B, BAP1 and TP53 alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify advanced RCC patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade, and develop personalized therapies.

Type: Other
Archive: European Genome-phenome Archive (EGA)

4 Datasets 18 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001006616	This dataset contains somatic alteration calls summarized at the gene level for 715 patients profiled by FoundationOne (Foundation Medicine).		1538
EGAD00001006617	This dataset contains demographic, histology, PDL1 IHC, TMB and outcome data (PFS and ORR) for 836 patients, 823 of which had RNAseq, 715 had FMI, with 702 patients having both. The dataset also includes xCell deconvolution scores for patients with RNAseq data.		1538
EGAD00001006618	This dataset contains log2(TPM + 1) transformed counts for the 823 tumor samples profiled by RNAseq.		1538
EGAD00001006619	This dataset contains FASTq files for tumors from the 823 patients profiled by RNAseq.	Illumina HiSeq 4000	823

Publications	Citations
Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Motzer RJ, Banchereau R, Hamidi H, Powles T, McDermott D, Atkins MB, Escudier B, Liu LF, Leng N, Abbas AR, Fan J, Koeppen H, Lin J, Carroll S, Hashimoto K, Mariathasan S, Green M, Tayama D, Hegde PS, Schiff C, Huseni MA, Rini B. Cancer Cell 38: 2020 803-817.e4	500
A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy. Büttner FA, Winter S, Stühler V, Rausch S, Hennenlotter J, Füssel S, Zastrow S, Meinhardt M, Toma M, Jerónimo C, Henrique R, Miranda-Gonçalves V, Kröger N, Ribback S, Hartmann A, Agaimy A, Stöhr C, Polifka I, Fend F, Scharpf M, Comperat E, Wasinger G, Moch H, Stenzl A, Gerlinger M, Bedke J, Schwab M, Schaeffeler E. Genome Med 14: 2022 105	30
Phagocytosis-Regulators-Based Signature to Predict the Prognosis and Chemotherapy Resistance for Breast Cancer Patients. Feng J, Ren J, Li X, Zhang X, Yang Q, Wu Z, Cui L, Liao L, Gong Y, Cao D. Int J Mol Sci 23: 2022 10312	11
A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy. Jiang A, Song J, Fang X, Fang Y, Wang Z, Liu B, Wu Z, Qu L, Luo P, Wang L. Front Public Health 10: 2022 1029509	7
A novel immune-related model to predict prognosis and responsiveness to checkpoint and angiogenesis blockade therapy in advanced renal cancer. Chen P, Bi F, Tan W, Jian L, Yu X. Front Oncol 13: 2023 1127448	5
Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression. Hu J, Wang SG, Hou Y, Chen Z, Liu L, Li R, Li N, Zhou L, Yang Y, Wang L, Wang L, Yang X, Lei Y, Deng C, Li Y, Deng Z, Ding Y, Kuang Y, Yao Z, Xun Y, Li F, Li H, Hu J, Liu Z, Wang T, Hao Y, Jiao X, Guan W, Tao Z, Ren S, Chen K. Nat Genet 56: 2024 442-457	135
Clear-Cell Renal Cell Carcinoma Molecular Subtypes Differ by African and European Genetic Similarity. Elias R, Nirschl T, Rezaee M, Yerrapragada A, Wang S, Cheaib J, Alam R, Patel S, Jing Y, Allaf M, McKean D, Klein AP, Fertig EJ, Baraban E, Ged Y, Yegnasubramanian S, Singla N. Cancer Res Commun 5: 2025 743-755	0
Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma. Mou W, Deng Z, Zhu L, Jiang A, Lin A, Xu L, Deng G, Huang H, Guo Z, Zhu B, Wu S, Yang T, Wang L, Liu Z, Wei T, Zhang J, Cheng L, Huang H, Chen R, Shao Y, Cheng Q, Wang L, Yuan S, Luo P. Sci Adv 11: 2025 eadu1727	28
Validation of a 15-Gene Prognostic Signature in Metastatic Clear Cell Renal Cell Carcinoma. Monda SM, Nallandhighal S, Vaishampayan U, Singhal U, Knuth Z, Mehra R, Kaffenberger S, Hafez K, Udager AM, Palapattu GS, Morgan TM, Salami SS. JCO Precis Oncol 9: 2025 e2500213	0
Interplay between tumor mutation burden and the tumor microenvironment predicts the prognosis of pan-cancer anti-PD-1/PD-L1 therapy. Liao W, Zhou X, Lin H, Feng Z, Chen X, Chen Y, Chen M, Lin M, Yao G, Chen J, Feng H, Wang Y, Tan Z, Tan Y, Lu J, Li P, Wei J, Luo L, Fu L. Front Immunol 16: 2025 1557461	4
Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell carcinoma. Salgia NJ, Khan A, Aubrecht WM, Twoey GC, Chow J, Attwood K, Yu H, Chiello JL, Hansen N, Wasik BJ, Mercier BD, Ebrahimi H, Meza L, Maguire O, Mastri M, Whalen C, Minderman H, Pirrotte P, Byron S, Repasky EA, Singh PK, Bshara W, Wang J, McGray AJR, Abrams SI, Xu B, Eng KH, Long MD, Pal SK, Kauffman EC, Muhitch JB. Cancer Cell 43: 2025 2014-2033.e9	14
AI-driven multimodal algorithm predicts immunotherapy and targeted therapy outcomes in clear cell renal cell carcinoma. Stupichev D, Miheecheva N, Postovalova E, Lyu Y, Ramachandran A, Galkin I, Khegai G, Perevoshchikova K, Love A, Menshikova S, Tarasov A, Svekolkin V, Bruttan M, Varlamova A, Kriukov K, Ataullakhanov R, Fowler N, Cheng E, Bagaev A, Hsieh JJ. Cell Rep Med 6: 2025 102299	7
Multi-Omics Profiling of Long Noncoding RNAs in Clear Cell Renal Cell Carcinoma for Characterization and Clinical Applications. Ding Y, Li Y, Liu Z, Hou Y, Yao Z, Shi P, Li J, Kuang Y, Liu Y, Hu J, Liu L, Chen K. Int J Biol Sci 22: 2026 3682-3700	0
Deciphering mitotic catastrophe-associated transcriptomic patterns in renal cell carcinoma: prognostic significance and immunotherapy-related associations. Wang Z, Hu X, Lin Z, Che F, Wei X, Zeng H. Biol Direct 21: 2026 167	0
Casdatifan shows durable response linked to HIF-2α biology in kidney cancer. Choueiri TK, Merchán J, Patnaik A, Drakaki A, Rini BI, Rha SY, Lee JL, Ornstein MC, Kumar R, Hwang C, Shao Y, Park SH, Barata PC, McGregor BA, Foster P, Chen J, Eisen M, Cole H, Weeder B, Guan Y, Singh J, Kaplan A, Cho S, Markus R, Kabbarah O, McKay RR. Nature 656: 2026 734-741	0
Integrative multi-omics analysis identifies SMIM24 as a favorable prognostic biomarker in clear cell renal cell carcinoma. Li Z, Liu Y, Hou Y, Ding Y, Liu Z, Li Y, Shi P, Li Y, Kuang Y, Zhou L, Chen K, Liu L. Funct Integr Genomics 26: 2026 225	0
Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma. Konda P, Wakolbinger AJ, Cui Y, Roberti de Oliveira G, Nabil YL, Weiss CN, Seager MD, Deodhar R, Li J, Matar S, Wang J, Horst J, Camp SY, Sheshdeh AB, Hecht JL, Einstein DJ, Rustagi Y, Nag A, Thorner AR, Zhang CZ, Van Allen EM, Signoretti S, Choueiri TK, Viswanathan SR. Nat Commun 17: 2026 10191	1
Stereotactic body radiation therapy enriches mediators of humoral immune activity in metastatic renal cell carcinoma. Salgia NJ, Khan A, Fujiwara Y, Long M, Twoey GC, Leatt K, Chow J, Abrams SI, Schwaab T, Singh AK, Muhitch JB. J Immunother Cancer 14: 2026 e015849	0