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

Research output: Contribution to journalArticlepeer-review

30 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 languageEnglish (US)
Pages (from-to)720-734.e13
JournalCancer cell
Volume37
Issue number5
DOIs
StatePublished - 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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