Integrative clinical and molecular characterization of translocation renal cell carcinoma

Ziad Bakouny; Ananthan Sadagopan; Praful Ravi; Nebiyou Y. Metaferia; Jiao Li; Shatha AbuHammad; Stephen Tang; Thomas Denize; Emma R. Garner; Xin Gao; David A. Braun; Laure Hirsch; John A. Steinharter; Gabrielle Bouchard; Emily Walton; Destiny West; Chris Labaki; Shaan Dudani; Chun Loo Gan; Vidyalakshmi Sethunath; Filipe L.F. Carvalho; Alma Imamovic; Cora Ricker; Natalie I. Vokes; Jackson Nyman; Jacob E. Berchuck; Jihye Park; Michelle S. Hirsch; Rizwan Haq; Gwo Shu Mary Lee; Bradley A. McGregor; Steven L. Chang; Adam S. Feldman; Catherine J. Wu; David F. McDermott; Daniel Y.C. Heng; Sabina Signoretti; Eliezer M. Van Allen; Toni K. Choueiri; Srinivas R. Viswanathan

doi:10.1016/j.celrep.2021.110190

Integrative clinical and molecular characterization of translocation renal cell carcinoma

Ziad Bakouny, Ananthan Sadagopan, Praful Ravi, Nebiyou Y. Metaferia, Jiao Li, Shatha AbuHammad, Stephen Tang, Thomas Denize, Emma R. Garner, Xin Gao, David A. Braun, Laure Hirsch, John A. Steinharter, Gabrielle Bouchard, Emily Walton, Destiny West, Chris Labaki, Shaan Dudani, Chun Loo Gan, Vidyalakshmi SethunathFilipe L.F. Carvalho, Alma Imamovic, Cora Ricker, Natalie I. Vokes, Jackson Nyman, Jacob E. Berchuck, Jihye Park, Michelle S. Hirsch, Rizwan Haq, Gwo Shu Mary Lee, Bradley A. McGregor, Steven L. Chang, Adam S. Feldman, Catherine J. Wu, David F. McDermott, Daniel Y.C. Heng, Sabina Signoretti, Eliezer M. Van Allen, Toni K. Choueiri, Srinivas R. Viswanathan

Thoracic Head & Neck Medical Oncology

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

41 Scopus citations

Abstract

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8⁺ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Original language	English (US)
Article number	110190
Journal	Cell Reports
Volume	38
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2021.110190
State	Published - Jan 4 2022

Keywords

MITF
NRF2
TFE3
TFEB
VEGFR
genomics
immune checkpoint inhibition
immunotherapy
oxidative stress
translocation renal cell carcinoma

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.110190

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Bakouny, Z., Sadagopan, A., Ravi, P., Metaferia, N. Y., Li, J., AbuHammad, S., Tang, S., Denize, T., Garner, E. R., Gao, X., Braun, D. A., Hirsch, L., Steinharter, J. A., Bouchard, G., Walton, E., West, D., Labaki, C., Dudani, S., Gan, C. L., ... Viswanathan, S. R. (2022). Integrative clinical and molecular characterization of translocation renal cell carcinoma. Cell Reports, 38(1), Article 110190. https://doi.org/10.1016/j.celrep.2021.110190

Bakouny, Z, Sadagopan, A, Ravi, P, Metaferia, NY, Li, J, AbuHammad, S, Tang, S, Denize, T, Garner, ER, Gao, X, Braun, DA, Hirsch, L, Steinharter, JA, Bouchard, G, Walton, E, West, D, Labaki, C, Dudani, S, Gan, CL, Sethunath, V, Carvalho, FLF, Imamovic, A, Ricker, C, Vokes, NI, Nyman, J, Berchuck, JE, Park, J, Hirsch, MS, Haq, R, Mary Lee, GS, McGregor, BA, Chang, SL, Feldman, AS, Wu, CJ, McDermott, DF, Heng, DYC, Signoretti, S, Van Allen, EM, Choueiri, TK & Viswanathan, SR 2022, 'Integrative clinical and molecular characterization of translocation renal cell carcinoma', Cell Reports, vol. 38, no. 1, 110190. https://doi.org/10.1016/j.celrep.2021.110190

@article{f2969c3f74bc45ac86517091cbb62d9f,

title = "Integrative clinical and molecular characterization of translocation renal cell carcinoma",

abstract = "Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8+ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.",

keywords = "MITF, NRF2, TFE3, TFEB, VEGFR, genomics, immune checkpoint inhibition, immunotherapy, oxidative stress, translocation renal cell carcinoma",

author = "Ziad Bakouny and Ananthan Sadagopan and Praful Ravi and Metaferia, {Nebiyou Y.} and Jiao Li and Shatha AbuHammad and Stephen Tang and Thomas Denize and Garner, {Emma R.} and Xin Gao and Braun, {David A.} and Laure Hirsch and Steinharter, {John A.} and Gabrielle Bouchard and Emily Walton and Destiny West and Chris Labaki and Shaan Dudani and Gan, {Chun Loo} and Vidyalakshmi Sethunath and Carvalho, {Filipe L.F.} and Alma Imamovic and Cora Ricker and Vokes, {Natalie I.} and Jackson Nyman and Berchuck, {Jacob E.} and Jihye Park and Hirsch, {Michelle S.} and Rizwan Haq and {Mary Lee}, {Gwo Shu} and McGregor, {Bradley A.} and Chang, {Steven L.} and Feldman, {Adam S.} and Wu, {Catherine J.} and McDermott, {David F.} and Heng, {Daniel Y.C.} and Sabina Signoretti and {Van Allen}, {Eliezer M.} and Choueiri, {Toni K.} and Viswanathan, {Srinivas R.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = jan,

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doi = "10.1016/j.celrep.2021.110190",

language = "English (US)",

volume = "38",

journal = "Cell Reports",

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T1 - Integrative clinical and molecular characterization of translocation renal cell carcinoma

AU - Bakouny, Ziad

AU - Sadagopan, Ananthan

AU - Ravi, Praful

AU - Metaferia, Nebiyou Y.

AU - Li, Jiao

AU - AbuHammad, Shatha

AU - Tang, Stephen

AU - Denize, Thomas

AU - Garner, Emma R.

AU - Gao, Xin

AU - Braun, David A.

AU - Hirsch, Laure

AU - Steinharter, John A.

AU - Bouchard, Gabrielle

AU - Walton, Emily

AU - West, Destiny

AU - Labaki, Chris

AU - Dudani, Shaan

AU - Gan, Chun Loo

AU - Sethunath, Vidyalakshmi

AU - Carvalho, Filipe L.F.

AU - Imamovic, Alma

AU - Ricker, Cora

AU - Vokes, Natalie I.

AU - Nyman, Jackson

AU - Berchuck, Jacob E.

AU - Park, Jihye

AU - Hirsch, Michelle S.

AU - Haq, Rizwan

AU - Mary Lee, Gwo Shu

AU - McGregor, Bradley A.

AU - Chang, Steven L.

AU - Feldman, Adam S.

AU - Wu, Catherine J.

AU - McDermott, David F.

AU - Heng, Daniel Y.C.

AU - Signoretti, Sabina

AU - Van Allen, Eliezer M.

AU - Choueiri, Toni K.

AU - Viswanathan, Srinivas R.

PY - 2022/1/4

Y1 - 2022/1/4

N2 - Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8+ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

AB - Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8+ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

KW - MITF

KW - NRF2

KW - TFE3

KW - TFEB

KW - VEGFR

KW - genomics

KW - immune checkpoint inhibition

KW - immunotherapy

KW - oxidative stress

KW - translocation renal cell carcinoma

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DO - 10.1016/j.celrep.2021.110190

M3 - Article

C2 - 34986355

AN - SCOPUS:85122005278

SN - 2211-1247

VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 110190

ER -

Integrative clinical and molecular characterization of translocation renal cell carcinoma

Abstract

Keywords

ASJC Scopus subject areas

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