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Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma
Jozefina Casuscelli, … , A. Ari Hakimi, James J. Hsieh
Jozefina Casuscelli, … , A. Ari Hakimi, James J. Hsieh
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e92688. https://doi.org/10.1172/jci.insight.92688.
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Research Article Genetics Oncology

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

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Abstract

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~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.

Authors

Jozefina Casuscelli, Nils Weinhold, Gunes Gundem, Lu Wang, Emily C. Zabor, Esther Drill, Patricia I. Wang, Gouri J. Nanjangud, Almedina Redzematovic, Amrita M. Nargund, Brandon J. Manley, Maria E. Arcila, Nicholas M. Donin, John C. Cheville, R. Houston Thompson, Allan J. Pantuck, Paul Russo, Emily H. Cheng, William Lee, Satish K. Tickoo, Irina Ostrovnaya, Chad J. Creighton, Elli Papaemmanuil, Venkatraman E. Seshan, A. Ari Hakimi, James J. Hsieh

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Figure 1

Whole-genome sequencing analysis of 5 metastatic chromophobe renal cell carcinoma (M-chRCC) cases in the exploratory cohort.

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Whole-genome sequencing analysis of 5 metastatic chromophobe renal cell ...
(A) Diagrams summarize the somatic alterations identified by the whole-genome sequencing (WGS) analysis of primary tumors from patients JHCHR3, JHCHR4, and JHCHR6. The uppermost track depicts inter- and intrachromosomal rearrangements as arcs. The copy number (CN) track shows the number of paternal and maternal copies of each chromosome (blue and red bars, respectively). The other tracks show total CN log-ratio (logR) and B allele frequency (BAF). See supplemental method for additional details. (B) Clonality analysis of 5 M-chRCC cases based on WGS data. Patient identification numbers are listed along with corresponding purity and ploidy estimates for the tumors generated with the Battenberg algorithm. Each branch represents a subclone and is annotated with alterations that could be assigned to the corresponding subclone. The length is proportional to the number of substitutions assigned by Dirichlet process clustering (see supplemental methods and Supplemental Figure 3 for details).

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