Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

Pavlos Msaouel; Gabriel G. Malouf; Xiaoping Su; Hui Yao; Durga N. Tripathi; Melinda Soeung; Jianjun Gao; Priya Rao; Cristian Coarfa; Chad J. Creighton; Jean Philippe Bertocchio; Selvi Kunnimalaiyaan; Asha S. Multani; Jorge Blando; Rong He; Daniel D. Shapiro; Luigi Perelli; Sanjana Srinivasan; Federica Carbone; Patrick G. Pilié; Menuka Karki; Riyad N.H. Seervai; Bujamin H. Vokshi; Dolores Lopez-Terrada; Emily H. Cheng; Ximing Tang; Wei Lu; Ignacio I. Wistuba; Timothy C. Thompson; Irwin Davidson; Virginia Giuliani; Katharina Schlacher; Alessandro Carugo; Timothy P. Heffernan; Padmanee Sharma; Jose A. Karam; Christopher G. Wood; Cheryl L. Walker; Giannicola Genovese; Nizar M. Tannir

doi:10.1016/j.ccell.2020.04.002

Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Melinda Soeung, Jianjun Gao, Priya Rao, Cristian Coarfa, Chad J. Creighton, Jean Philippe Bertocchio, Selvi Kunnimalaiyaan, Asha S. Multani, Jorge Blando, Rong He, Daniel D. Shapiro, Luigi Perelli, Sanjana Srinivasan, Federica Carbone, Patrick G. PiliéMenuka Karki, Riyad N.H. Seervai, Bujamin H. Vokshi, Dolores Lopez-Terrada, Emily H. Cheng, Ximing Tang, Wei Lu, Ignacio I. Wistuba, Timothy C. Thompson, Irwin Davidson, Virginia Giuliani, Katharina Schlacher, Alessandro Carugo, Timothy P. Heffernan, Padmanee Sharma, Jose A. Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir

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66 Scopus citations

Abstract

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy. Msaouel et al. describe the molecular landscape of renal medullary carcinomas (RMC). These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors. cGAS-STING activation in RMCs warrants exploration of immunotherapy for these patients.

Original language	English (US)
Pages (from-to)	720-734.e13
Journal	Cancer cell
Volume	37
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2020.04.002
State	Published - May 11 2020

Keywords

SMARCB1
cGAS-STING pathway
molecular profiling
renal medullary carcinoma
replication stress

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource
Cytogenetics and Cell Authentication Core

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10.1016/j.ccell.2020.04.002

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Msaouel, P., Malouf, G. G., Su, X., Yao, H., Tripathi, D. N., Soeung, M., Gao, J., Rao, P., Coarfa, C., Creighton, C. J., Bertocchio, J. P., Kunnimalaiyaan, S., Multani, A. S., Blando, J., He, R., Shapiro, D. D., Perelli, L., Srinivasan, S., Carbone, F., ... Tannir, N. M. (2020). Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma. Cancer cell, 37(5), 720-734.e13. https://doi.org/10.1016/j.ccell.2020.04.002

Msaouel, P, Malouf, GG, Su, X, Yao, H, Tripathi, DN, Soeung, M, Gao, J , Rao, P, Coarfa, C, Creighton, CJ, Bertocchio, JP, Kunnimalaiyaan, S, Multani, AS, Blando, J, He, R, Shapiro, DD, Perelli, L, Srinivasan, S, Carbone, F, Pilié, PG , Karki, M, Seervai, RNH, Vokshi, BH, Lopez-Terrada, D, Cheng, EH, Tang, X , Lu, W , Wistuba, II , Thompson, TC, Davidson, I, Giuliani, V , Schlacher, K, Carugo, A, Heffernan, TP, Sharma, P , Karam, JA, Wood, CG, Walker, CL, Genovese, G & Tannir, NM 2020, 'Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma', Cancer cell, vol. 37, no. 5, pp. 720-734.e13. https://doi.org/10.1016/j.ccell.2020.04.002

@article{d7cbe5d1f26c4ac482b23bebe954a06f,

title = "Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma",

abstract = "Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy. Msaouel et al. describe the molecular landscape of renal medullary carcinomas (RMC). These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors. cGAS-STING activation in RMCs warrants exploration of immunotherapy for these patients.",

keywords = "SMARCB1, cGAS-STING pathway, molecular profiling, renal medullary carcinoma, replication stress",

author = "Pavlos Msaouel and Malouf, {Gabriel G.} and Xiaoping Su and Hui Yao and Tripathi, {Durga N.} and Melinda Soeung and Jianjun Gao and Priya Rao and Cristian Coarfa and Creighton, {Chad J.} and Bertocchio, {Jean Philippe} and Selvi Kunnimalaiyaan and Multani, {Asha S.} and Jorge Blando and Rong He and Shapiro, {Daniel D.} and Luigi Perelli and Sanjana Srinivasan and Federica Carbone and Pili{\'e}, {Patrick G.} and Menuka Karki and Seervai, {Riyad N.H.} and Vokshi, {Bujamin H.} and Dolores Lopez-Terrada and Cheng, {Emily H.} and Ximing Tang and Wei Lu and Wistuba, {Ignacio I.} and Thompson, {Timothy C.} and Irwin Davidson and Virginia Giuliani and Katharina Schlacher and Alessandro Carugo and Heffernan, {Timothy P.} and Padmanee Sharma and Karam, {Jose A.} and Wood, {Christopher G.} and Walker, {Cheryl L.} and Giannicola Genovese and Tannir, {Nizar M.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = may,

day = "11",

doi = "10.1016/j.ccell.2020.04.002",

language = "English (US)",

volume = "37",

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T1 - Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

AU - Msaouel, Pavlos

AU - Malouf, Gabriel G.

AU - Su, Xiaoping

AU - Yao, Hui

AU - Tripathi, Durga N.

AU - Soeung, Melinda

AU - Gao, Jianjun

AU - Rao, Priya

AU - Coarfa, Cristian

AU - Creighton, Chad J.

AU - Bertocchio, Jean Philippe

AU - Kunnimalaiyaan, Selvi

AU - Multani, Asha S.

AU - Blando, Jorge

AU - He, Rong

AU - Shapiro, Daniel D.

AU - Perelli, Luigi

AU - Srinivasan, Sanjana

AU - Carbone, Federica

AU - Pilié, Patrick G.

AU - Karki, Menuka

AU - Seervai, Riyad N.H.

AU - Vokshi, Bujamin H.

AU - Lopez-Terrada, Dolores

AU - Cheng, Emily H.

AU - Tang, Ximing

AU - Lu, Wei

AU - Wistuba, Ignacio I.

AU - Thompson, Timothy C.

AU - Davidson, Irwin

AU - Giuliani, Virginia

AU - Schlacher, Katharina

AU - Carugo, Alessandro

AU - Heffernan, Timothy P.

AU - Sharma, Padmanee

AU - Karam, Jose A.

AU - Wood, Christopher G.

AU - Walker, Cheryl L.

AU - Genovese, Giannicola

AU - Tannir, Nizar M.

PY - 2020/5/11

Y1 - 2020/5/11

N2 - Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy. Msaouel et al. describe the molecular landscape of renal medullary carcinomas (RMC). These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors. cGAS-STING activation in RMCs warrants exploration of immunotherapy for these patients.

AB - Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy. Msaouel et al. describe the molecular landscape of renal medullary carcinomas (RMC). These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors. cGAS-STING activation in RMCs warrants exploration of immunotherapy for these patients.

KW - SMARCB1

KW - cGAS-STING pathway

KW - molecular profiling

KW - renal medullary carcinoma

KW - replication stress

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VL - 37

SP - 720-734.e13

JO - Cancer cell

JF - Cancer cell

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ER -

Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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