Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Ziad Bakouny, David A. Braun, Sachet A. Shukla, Wenting Pan, Xin Gao, Yue Hou, Abdallah Flaifel, Stephen Tang, Alice Bosma-Moody, Meng Xiao He, Natalie Vokes, Jackson Nyman, Wanling Xie, Amin H. Nassar, Sarah Abou Alaiwi, Ronan Flippot, Gabrielle Bouchard, John A. Steinharter, Pier Vitale Nuzzo, Miriam Ficial, Miriam Sant’Angelo, Juliet Forman, Jacob E. Berchuck, Shaan Dudani, Kevin Bi, Jihye Park, Sabrina Camp, Maura Sticco-Ivins, Laure Hirsch, Sylvan C. Baca, Megan Wind-Rotolo, Petra Ross-Macdonald, Maxine Sun, Gwo-Shu Mary Lee, Steven L. Chang, Xiao X. Wei, Bradley A. McGregor, Lauren C. Harshman, Giannicola Genovese, Leigh Ellis, Mark Pomerantz, Michelle S. Hirsch, Matthew L. Freedman, Michael B. Atkins, Catherine J. Wu, Thai H. Ho, W. Marston Linehan, David F. McDermott, Daniel Y. C. Heng, Srinivas R. Viswanathan, Sabina Signoretti, Eliezer M. Van Allen () and Toni K. Choueiri ()
Additional contact information
Ziad Bakouny: Dana-Farber Cancer Institute
David A. Braun: Dana-Farber Cancer Institute
Sachet A. Shukla: Dana-Farber Cancer Institute
Wenting Pan: Dana-Farber Cancer Institute
Xin Gao: Department of Medicine, Massachusetts General Hospital Cancer Center
Yue Hou: Dana-Farber Cancer Institute
Abdallah Flaifel: Department of Pathology, Brigham and Women’s Hospital
Stephen Tang: Dana-Farber Cancer Institute
Alice Bosma-Moody: Dana-Farber Cancer Institute
Meng Xiao He: Dana-Farber Cancer Institute
Natalie Vokes: Dana-Farber Cancer Institute
Jackson Nyman: Dana-Farber Cancer Institute
Wanling Xie: Department of Data Sciences, Dana-Farber Cancer Institute
Amin H. Nassar: Dana-Farber Cancer Institute
Sarah Abou Alaiwi: Dana-Farber Cancer Institute
Ronan Flippot: Dana-Farber Cancer Institute
Gabrielle Bouchard: Dana-Farber Cancer Institute
John A. Steinharter: Dana-Farber Cancer Institute
Pier Vitale Nuzzo: Dana-Farber Cancer Institute
Miriam Ficial: Department of Pathology, Brigham and Women’s Hospital
Miriam Sant’Angelo: Department of Pathology, Brigham and Women’s Hospital
Juliet Forman: Dana-Farber Cancer Institute
Jacob E. Berchuck: Dana-Farber Cancer Institute
Shaan Dudani: University of Calgary
Kevin Bi: Dana-Farber Cancer Institute
Jihye Park: Dana-Farber Cancer Institute
Sabrina Camp: Dana-Farber Cancer Institute
Maura Sticco-Ivins: Department of Pathology, Brigham and Women’s Hospital
Laure Hirsch: Dana-Farber Cancer Institute
Sylvan C. Baca: Dana-Farber Cancer Institute
Megan Wind-Rotolo: Bristol-Myers Squibb
Petra Ross-Macdonald: Bristol-Myers Squibb
Maxine Sun: Dana-Farber Cancer Institute
Gwo-Shu Mary Lee: Dana-Farber Cancer Institute
Steven L. Chang: Dana-Farber Cancer Institute
Xiao X. Wei: Dana-Farber Cancer Institute
Bradley A. McGregor: Dana-Farber Cancer Institute
Lauren C. Harshman: Dana-Farber Cancer Institute
Giannicola Genovese: The University of Texas MD Anderson Cancer Center
Leigh Ellis: Department of Pathology, Brigham and Women’s Hospital
Mark Pomerantz: Dana-Farber Cancer Institute
Michelle S. Hirsch: Department of Pathology, Brigham and Women’s Hospital
Matthew L. Freedman: Dana-Farber Cancer Institute
Michael B. Atkins: Georgetown University Medical Center
Catherine J. Wu: Dana-Farber Cancer Institute
Thai H. Ho: Division of Hematology and Medical Oncology, Mayo Clinic
W. Marston Linehan: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH
David F. McDermott: Beth Israel Deaconess Medical Center
Daniel Y. C. Heng: University of Calgary
Srinivas R. Viswanathan: Dana-Farber Cancer Institute
Sabina Signoretti: Department of Pathology, Brigham and Women’s Hospital
Eliezer M. Van Allen: Dana-Farber Cancer Institute
Toni K. Choueiri: Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21068-9

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DOI: 10.1038/s41467-021-21068-9

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