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, Pavlos and Malouf, Gabriel G. and Su, Xiaoping and Yao, Hui and Tripathi, Durga N. and Gao, Jianjun and Rao, Priya and Coarfa, Cristian and Creighton, Chad J. and Multani, Asha S. and Blando, Jorge and He, Rong and Soeung, Melinda and Perelli, Luigi and Srinivasan, Sanjana and Bertocchio, Jean-Philippe and Pilié, Patrick G. and Karki, Menuka and Seervai, Riyad N.H. and Lopez-Terrada, Dolores and Tang, Ximing and Lu, Wei and Wistuba, Ignacio I. and Giuliani, Virginia and Carugo, Alessandro and Heffernan, Timothy P. and Sharma, Padmanee and Karam, Jose A. and Wood, Christopher G. and Walker, Cheryl L. and Genovese, Giannicola and Tannir, Nizar M., Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma (September 16, 2019). Available at SSRN: https://ssrn.com/abstract=3454866 or http://dx.doi.org/10.2139/ssrn.3454866
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