@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 = "Funding Information: We thank Dr. Waun Ki Hong for discussions and suggestions. We thank Dr. Bernard E. Weissman for discussions and reagents. We thank Dr. Bora Lim for creative assistance with illustrations. We thank the UTMDACC Advanced Technology Genomics Core (ATGC) and the Cytogenetics and Cell Authentication Core. We thank Thomas Huynh and the UTMDACC Department of Veterinary Medicine & Surgery Anatomic Pathology Laboratory. This work was supported in part by the Cancer Center support grant to MDACC (grant number P30 CA016672 ) from the National Cancer Institute of the National Institutes of Health , and by philanthropic donations from the Chris “CJ” Johnson Foundation Inc and RMC Inc. P.M. was supported by a Conquer Cancer Foundation Young Investigator award, a Kidney Cancer Association Young Investigator award, a United States Department of Defense Concept award, and the National Institutes of Health grant T32 CA009666 . J.-P.B. and B.H.V. were funded by La Ligue Nationale Contre le Cancer . J.-P.B. was also supported by the Philip Foundation . I.D. is an {\textquoteleft}{\'e}quipe lab{\'e}lis{\'e}e{\textquoteright} of the Ligue Nationale contre le Cancer . S.S. was supported by the CPRIT research training grant RP170067 . C.C. and C.J.C. were supported by the NIH grant CA125123 . F.C. is supported by the Italian Association for Cancer Research AIRC for abroad fellowship. R.N.H.S. is supported by an American Heart Association predoctoral fellowship 19PRE34430069 . K.S. is supported by grants NIH 1R01ES029680 , CPRIT RP180813 , and RP180463 , and is a Rita Allen Fellow and a CPRIT Scholar in Cancer Biology. Funding Information: We thank Dr. Waun Ki Hong for discussions and suggestions. We thank Dr. Bernard E. Weissman for discussions and reagents. We thank Dr. Bora Lim for creative assistance with illustrations. We thank the UTMDACC Advanced Technology Genomics Core (ATGC) and the Cytogenetics and Cell Authentication Core. We thank Thomas Huynh and the UTMDACC Department of Veterinary Medicine & Surgery Anatomic Pathology Laboratory. This work was supported in part by the Cancer Center support grant to MDACC (grant number P30 CA016672) from the National Cancer Institute of the National Institutes of Health, and by philanthropic donations from the Chris ?CJ? Johnson Foundation Inc and RMC Inc. P.M. was supported by a Conquer Cancer Foundation Young Investigator award, a Kidney Cancer Association Young Investigator award, a United States Department of Defense Concept award, and the National Institutes of Health grant T32 CA009666. J.-P.B. and B.H.V. were funded by La Ligue Nationale Contre le Cancer. J.-P.B. was also supported by the Philip Foundation. I.D. is an ??quipe lab?lis?e? of the Ligue Nationale contre le Cancer. S.S. was supported by the CPRIT research training grant RP170067. C.C. and C.J.C. were supported by the NIH grant CA125123. F.C. is supported by the Italian Association for Cancer Research AIRC for abroad fellowship. R.N.H.S. is supported by an American Heart Association predoctoral fellowship 19PRE34430069. K.S. is supported by grants NIH 1R01ES029680, CPRIT RP180813, and RP180463, and is a Rita Allen Fellow and a CPRIT Scholar in Cancer Biology. Conceptualization, P.M. G.G.M. C.L.W. G.G. and N.M.T.; Methodology, P.M. G.G.M. X.S. H.Y. D.N.T. J.J.G. C.C. C.J.C. P.G.P. M.S. S.S. J.-P.B. D.D.S. R.N.H.S. S.K. K.S. B.H.V. C.L.W. G.G. and N.M.T.; Formal Analysis, P.M. G.G.M. X.S. H.Y. D.N.T. C.C. C.J.C. M.S. S.S. J.-P.B. D.D.S. R.N.H.S. S.K. and K.S.; Investigation, P.M. G.G.M. D.N.T. P.R. A.S.M. X.T. I.I.W. R.H. M.S. L.P. J.-P.B. D.D.S. M.K. R.N.H.S. B.H.V. D.L.-T. W.L. V.G. A.C. T.P.H. P.S. J.A.K. C.G.W. C.L.W. G.G. and N.M.T.; Writing ? Original Draft, P.M. G.G. and C.L.W; Writing ? Review and Editing, P.M. G.G.M. X.S. H.Y. D.N.T. J.J.G. P.R. C.C. C.J.C. A.S.M. J.B. D.D.S. M.S. L.P. S.S. J.-P.B. P.G.P. R.N.H.S. D.L.-T. I.I.W. V.G. A.C. T.P.H. P.S. J.A.K. C.G.W. C.L.W. G.G. and N.M.T.; Resources, P.M. G.G.M. X.S. H.Y. D.N.T. C.C. C.J.C. A.S.M. J.B. R.H. M.S. L.P. J.-P.B. D.D.S. F.C. M.K. R.N.H.S. D.L.-T. E.H.C. X.T. W.L. I.I.W. T.C.T. I.D. V.G. A.C. T.P.H. P.S. C.L.W. G.G. and N.M.T.; Supervision, P.M. C.L.W. G.G. and N.M.T.; Funding Acquisition, P.M. C.L.W. G.G. and N.M.T. The authors declare no competing interests. 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",
pages = "720--734.e13",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}