Comprehensive genomic analysis of translocation renal cell carcinoma reveals copy-number variations as drivers of disease progression Journal Article


Authors: Marcon, J.; DiNatale, R. G.; Sanchez, A.; Kotecha, R. R.; Gupta, S.; Kuo, F.; Makarov, V.; Sandhu, A.; Mano, R.; Silagy, A. W.; Blum, K. A.; Nassau, D. E.; Benfante, N. E.; Ortiz, M. V.; Carlo, M. I.; Chan, T. A.; Motzer, R. J.; Voss, M. H.; Coleman, J.; Russo, P.; Reuter, V.; Hakimi, A. A.; Reznik, E.
Article Title: Comprehensive genomic analysis of translocation renal cell carcinoma reveals copy-number variations as drivers of disease progression
Abstract: PURPOSE: Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing. EXPERIMENTAL DESIGN: Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number-altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan-Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing. RESULTS: Copy-number aberrant tRCCs were associated with poor overall survival (P = 0.03). Pediatric patients had tumors with lower FCNAg (P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes. CONCLUSIONS: Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration. ©2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 26
Issue: 14
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2020-07-15
Start Page: 3629
End Page: 3640
Language: English
DOI: 10.1158/1078-0432.Ccr-19-3283
PUBMED: 32220885
PROVIDER: scopus
PMCID: PMC7367714
DOI/URL:
Notes: Article -- Export Date: 3 August 2020 -- Source: Scopus
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MSK Authors
  1. Jonathan Coleman
    347 Coleman
  2. Timothy Chan
    317 Chan
  3. Paul Russo
    582 Russo
  4. Robert Motzer
    1247 Motzer
  5. Martin Henner Voss
    293 Voss
  6. Victor Reuter
    1229 Reuter
  7. Abraham Ari Hakimi
    327 Hakimi
  8. Maria Isabel Carlo
    165 Carlo
  9. Roy Mano
    52 Mano
  10. Eduard Reznik
    108 Reznik
  11. Vladimir Makarov
    57 Makarov
  12. Michael Vincent Ortiz
    62 Ortiz
  13. Nicole E Benfante
    162 Benfante
  14. Fengshen Kuo
    81 Kuo
  15. Sounak Gupta
    32 Gupta
  16. Alejandro Sanchez
    29 Sanchez
  17. Kyle Blum
    38 Blum
  18. Andrew William Silagy
    33 Silagy
  19. Julian Marcon
    19 Marcon
  20. Ritesh Rajesh Kotecha
    94 Kotecha
  21. Amar Singh Sandhu
    1 Sandhu
  22. Daniel E. Nassau
    1 Nassau