Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

• DOI: 10.1101/2021.04.14.439908
• Publication Date: 2021-04-16T05:06:56Z
• Authors: Ziad Bakouny; Ananthan Sadagopan; Praful Ravi; Nebiyou Y. Metaferia; Jiao Li; Shatha AbuHammad; Stephen Tang; Thomas Denize; Emma R. Garner; Xin Gao; David A. Braun; Laure Hirsch; John A. Steinharter; Gabrielle Bouchard; Emily Walton; Destiny West; Chris Labaki; Shaan Dudani; Chun-Loo Gan; Vidyalakshmi Seth...; Filipe LF. Carvalho; Alma Imamovic; Cora Ricker; Natalie I. Vokes; Jackson Nyman; Jihye Park; Michelle S. Hirsch; Rizwan Haq; Gwo-Shu Mary Lee; Bradley A. McGregor; Steven L. Chang; Adam S. Feldman; Catherine J. Wu; David F. McDermott; Daniel Y.C. Heng; Sabina Signoretti; Eliezer M. Van Allen; Toni K. Choueiri; Srinivas R. Viswa...
• Keywords: Immunophenotyping; Kidney cancer; Breakpoint

ABSTRACT Translocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks tRCC through integrative analysis 152 patients identified across multiple genomic, clinical trial, retrospective cohorts. Most tRCCs harbor few somatic alterations apart from fusions homozygous deletions at chromosome 9p21.3 (19.2% cases). Transcriptionally, display a heightened NRF2-driven antioxidant response that associated with resistance to many targeted therapies. Consistently, find outcomes for treated vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed presence CD8 + tumor-infiltrating T cells compatible benefit ICI revealed exhaustion immunophenotype distinct clear RCC. Our findings comprehensively molecular features may inspire new therapeutic hypotheses.