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

Cancer Cell. 2020 May 11;37(5):720-734.e13. doi: 10.1016/j.ccell.2020.04.002. | PubMed

Pavlos Msaouel¹, Gabriel G Malouf², Xiaoping Su³, Hui Yao³, Durga N Tripathi⁴, Melinda Soeung⁵, Jianjun Gao⁶, Priya Rao⁷, Cristian Coarfa⁸, Chad J Creighton⁹, Jean-Philippe Bertocchio¹⁰, Selvi Kunnimalaiyaan¹¹, Asha S Multani¹², Jorge Blando¹³, Rong He⁶, Daniel D Shapiro¹⁴, Luigi Perelli⁶, Sanjana Srinivasan¹⁵, Federica Carbone⁶, Patrick G Pilié⁶, Menuka Karki⁴, Riyad N H Seervai¹⁶, Bujamin H Vokshi², Dolores Lopez-Terrada¹⁷, Emily H Cheng¹⁸, Ximing Tang¹⁹, Wei Lu¹⁹, Ignacio I Wistuba¹⁹, Timothy C Thompson⁶, Irwin Davidson²⁰, Virginia Giuliani²¹, Katharina Schlacher¹¹, Alessandro Carugo²¹, Timothy P Heffernan²¹, Padmanee Sharma²², Jose A Karam²³, Christopher G Wood¹⁴, Cheryl L Walker²⁴, Giannicola Genovese²⁵, Nizar M Tannir²⁶

1. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA. Electronic address: pmsaouel@mdanderson.org.
2. Department of Hematology and Oncology, Strasbourg University Hospitals, Strasbourg University, Strasbourg, France; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, Illkirch Cedex, France.
3. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4. Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.
5. Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
6. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA.
7. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
8. Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
9. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
10. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.
11. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
12. Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
13. Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
14. Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
15. Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
16. Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA; Molecular & Cellular Biology Graduate Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
17. Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
18. Human Oncology & Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Institute, New York City, NY 10065, USA.
19. Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
20. Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, Illkirch Cedex, France.
21. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
22. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA; Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
23. Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
24. Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. Electronic address: cheryl.walker@bcm.edu.
25. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA; Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: ggenovese@mdanderson.org.
26. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA. Electronic address: ntannir@mdanderson.org.

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.

Presented By Pavlos Msaouel