Comprehensive genomic analysis of metastatic non-clear-cell renal cell carcinoma to identify therapeutic targets Journal Article


Authors: Carlo, M. I.; Khan, N.; Zehir, A.; Patil, S.; Ged, Y.; Redzematovic, A.; Coskey, D. T.; Hyman, D. M.; Ladanyi, M.; Chen, Y. B.; Robson, M.; Hakimi, A. A.; Lee, C. H.; Feldman, D. R.; Gao, J.; Chakravarty, D.; Motzer, R. J.; Voss, M. H.
Article Title: Comprehensive genomic analysis of metastatic non-clear-cell renal cell carcinoma to identify therapeutic targets
Abstract: PURPOSE Non-clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor- and mammalian target of rapamycin-directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies. PATIENTS AND METHODS We retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated. RESULTS Of 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in MET, TSC1/2, and an ALK translocation. Of 45 patients who had germline testing, 11 (24%) harbored mutations, seven of which could potentially guide therapy. Of 115 available tumors for analysis, two (1.7%) had high and six (5%) had intermediate MSI status. CONCLUSION The mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation. (C) 2019 by American Society of Clinical Oncology
Keywords: sunitinib; management; everolimus; phase-ii; multicenter; cancers; nivolumab; trk
Journal Title: JCO Precision Oncology
Volume: 3
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2019-04-28
Language: English
ACCESSION: WOS:000493745800001
DOI: 10.1200/po.18.00372
PROVIDER: wos
Notes: Article -- Source: Wos
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MSK Authors
  1. Sujata Patil
    432 Patil
  2. Robert Motzer
    887 Motzer
  3. Mark E Robson
    436 Robson
  4. Darren Richard Feldman
    214 Feldman
  5. Marc Ladanyi
    1000 Ladanyi
  6. Martin Henner Voss
    159 Voss
  7. Yingbei Chen
    264 Chen
  8. David Hyman
    279 Hyman
  9. Ahmet Zehir
    195 Zehir
  10. Jianjiong Gao
    72 Gao
  11. Abraham Ari Hakimi
    170 Hakimi
  12. Maria Isabel Carlo
    43 Carlo
  13. Chung-Han   Lee
    59 Lee
  14. Devyn Taylor Coskey
    13 Coskey
  15. Nabeela Ali Khan
    10 Khan
  16. Yasser Mohamed Ali Ged
    9 Ged