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; Toni K. Choueiri

doi:10.1038/s41467-021-21068-9

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 FicialMiriam 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, Toni K. Choueiri

Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	808
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21068-9
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Bakouny, Z., Braun, D. A., Shukla, S. A., Pan, W., Gao, X., Hou, Y., Flaifel, A., Tang, S., Bosma-Moody, A., He, M. X., Vokes, N., Nyman, J., Xie, W., Nassar, A. H., Abou Alaiwi, S., Flippot, R., Bouchard, G., Steinharter, J. A., Nuzzo, P. V., ... Choueiri, T. K. (2021). Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nature communications, 12(1), Article 808. https://doi.org/10.1038/s41467-021-21068-9

Bakouny, Z, Braun, DA, Shukla, SA, Pan, W, Gao, X, Hou, Y, Flaifel, A, Tang, S, Bosma-Moody, A, He, MX, Vokes, N, Nyman, J, Xie, W, Nassar, AH, Abou Alaiwi, S, Flippot, R, Bouchard, G, Steinharter, JA, Nuzzo, PV, Ficial, M, Sant’Angelo, M, Forman, J, Berchuck, JE, Dudani, S, Bi, K, Park, J, Camp, S, Sticco-Ivins, M, Hirsch, L, Baca, SC, Wind-Rotolo, M, Ross-Macdonald, P, Sun, M, Lee, GSM, Chang, SL, Wei, XX, McGregor, BA, Harshman, LC, Genovese, G, Ellis, L, Pomerantz, M, Hirsch, MS, Freedman, ML, Atkins, MB, Wu, CJ, Ho, TH, Linehan, WM, McDermott, DF, Heng, DYC, Viswanathan, SR, Signoretti, S, Van Allen, EM & Choueiri, TK 2021, 'Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma', Nature communications, vol. 12, no. 1, 808. https://doi.org/10.1038/s41467-021-21068-9

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title = "Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma",

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.",

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

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doi = "10.1038/s41467-021-21068-9",

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AU - Bakouny, Ziad

AU - Braun, David A.

AU - Shukla, Sachet A.

AU - Pan, Wenting

AU - Gao, Xin

AU - Hou, Yue

AU - Flaifel, Abdallah

AU - Tang, Stephen

AU - Bosma-Moody, Alice

AU - He, Meng Xiao

AU - Vokes, Natalie

AU - Nyman, Jackson

AU - Xie, Wanling

AU - Nassar, Amin H.

AU - Abou Alaiwi, Sarah

AU - Flippot, Ronan

AU - Bouchard, Gabrielle

AU - Steinharter, John A.

AU - Nuzzo, Pier Vitale

AU - Ficial, Miriam

AU - Sant’Angelo, Miriam

AU - Forman, Juliet

AU - Berchuck, Jacob E.

AU - Dudani, Shaan

AU - Bi, Kevin

AU - Park, Jihye

AU - Camp, Sabrina

AU - Sticco-Ivins, Maura

AU - Hirsch, Laure

AU - Baca, Sylvan C.

AU - Wind-Rotolo, Megan

AU - Ross-Macdonald, Petra

AU - Sun, Maxine

AU - Lee, Gwo Shu Mary

AU - Chang, Steven L.

AU - Wei, Xiao X.

AU - McGregor, Bradley A.

AU - Harshman, Lauren C.

AU - Genovese, Giannicola

AU - Ellis, Leigh

AU - Pomerantz, Mark

AU - Hirsch, Michelle S.

AU - Freedman, Matthew L.

AU - Atkins, Michael B.

AU - Wu, Catherine J.

AU - Ho, Thai H.

AU - Linehan, W. Marston

AU - McDermott, David F.

AU - Heng, Daniel Y.C.

AU - Viswanathan, Srinivas R.

AU - Signoretti, Sabina

AU - Van Allen, Eliezer M.

AU - Choueiri, Toni K.

PY - 2021/12/1

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N2 - 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.

AB - 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.

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Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Abstract

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