Journal Article

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Sant’Angelo, Miriam, Ross-Macdonald, Petra, Atkins, Michael B., Nuzzo, Pier Vitale, Tang, Stephen, Choueiri, Toni K., Hou, Yue, Flaifel, Abdallah, Ho, Thai H., Flippot, Ronan, Ellis, Leigh, Xie, Wanling, Shukla, Sachet A., Lee, Gwo-Shu Mary, Pan, Wenting, Park, Jihye, Camp, Sabrina, Dudani, Shaan, Signoretti, Sabina, Berchuck, Jacob E., Hirsch, Michelle S., Steinharter, John A., Sun, Maxine, McDermott, David F., Ficial, Miriam, Wei, Xiao X., Heng, Daniel Y. C., Pomerantz, Mark, McGregor, Bradley A., Viswanathan, Srinivas R., Bosma-Moody, Alice, Baca, Sylvan C., Forman, Juliet, Vokes, Natalie, Bi, Kevin, Nassar, Amin H., Hirsch, Laure, Bakouny, Ziad, Gao, Xin, Van Allen, Eliezer M., Bouchard, Gabrielle, He, Meng Xiao, Braun, David A., Nyman, Jackson, Wu, Catherine J., Sticco-Ivins, Maura, Genovese, Giannicola, Chang, Steven L., Wind-Rotolo, Megan, Linehan, W. Marston, Harshman, Lauren C., Freedman, Matthew L., Abou Alaiwi, Sarah

2021

Overview

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC. Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/23 / 38/91 / 45 / 45/23 / 45/91 / 631/250/251/1567 / 631/67/2329 / 631/67/580 / 631/67/589/1588/1351 / 631/67/69 / 82/51 / Antigen presentation / Antigens / Antineoplastic Agents, Immunological - therapeutic use / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Biological properties / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - immunology / Carcinoma, Renal Cell - mortality / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - genetics / CTLA-4 Antigen - immunology / Cyclin-Dependent Kinase Inhibitor p16 - genetics / Cyclin-Dependent Kinase Inhibitor p16 - immunology / Cytotoxicity / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - therapeutic use / Immune Checkpoint Proteins - genetics / Immune Checkpoint Proteins - immunology / Immune response / Immunotherapy / Inflammation / Kidney cancer / Kidney Neoplasms - drug therapy / Kidney Neoplasms - genetics / Kidney Neoplasms - immunology / Kidney Neoplasms - mortality / Metastases / multidisciplinary / Mutation / Myc protein / PD-L1 protein / Phenotypes / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - immunology / Renal cell carcinoma / Retrospective Studies / Rhabdoid Tumor - drug therapy / Rhabdoid Tumor - genetics / Rhabdoid Tumor - immunology / Rhabdoid Tumor - mortality / Science / Science (multidisciplinary) / Signal Transduction / Survival Analysis / Transcription / Transcription, Genetic / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - immunology / Tumors / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - immunology