Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma Journal Article

Authors: Casuscelli, J.; Weinhold, N.; Gundem, G.; Wang, L.; Zabor, E. C.; Drill, E.; Wang, P. I.; Nanjangud, G. J.; Redzematovic, A.; Nargund, A. M.; Manley, B. J.; Arcila, M. E.; Donin, N. M.; Cheville, J. C.; Thompson, R. H.; Pantuck, A. J.; Russo, P.; Cheng, E. H.; Lee, W.; Tickoo, S. K.; Ostrovnaya, I.; Creighton, C. J.; Papaemmanuil, E.; Seshan, V. E.; Hakimi, A. A.; Hsieh, J. J.
Article Title: Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma
Abstract: Chromophobe renal cell carcinoma (chRCC) typically shows similar to 7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and similar to 31 exonic somatic mutations, yet carries similar to 5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of >= 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
Keywords: classification; therapy; surveillance; mutations; hybridization; cancer genome; heterogeneity; copy number; tool; clonal evolution
Journal Title: JCI Insight
Volume: 2
Issue: 12
ISSN: 2379-3708
Publisher: Amer Soc Clinical Investigation Inc  
Date Published: 2017-06-15
Start Page: e92688
Language: English
ACCESSION: WOS:000403495200006
DOI: 10.1172/jci.insight.92688
PMCID: PMC5470887
PUBMED: 28614790
Notes: Article -- Source: Wos
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    285 Seshan
  2. Paul Russo
    449 Russo
  3. Satish K Tickoo
    369 Tickoo
  4. Emily Craig Zabor
    131 Zabor
  5. Lu Wang
    139 Wang
  6. Emily H Cheng
    55 Cheng
  7. Maria Eugenia Arcila
    343 Arcila
  8. William Lee
    38 Lee
  9. Abraham Ari Hakimi
    129 Hakimi
  10. Esther Naomi Drill
    25 Drill
  11. Patricia Ibai Wang
    12 Wang
  12. Brandon John Manley
    21 Manley
  13. Gunes Gundem
    11 Gundem