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 |
| PROVIDER: | wos |
| PMCID: | PMC5470887 |
| PUBMED: | 28614790 |
| Notes: | Article -- Source: Wos |
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