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Casuscelli, Jozefina; Weinhold, Nils; Gundem, Gunes; Wang, Lu; Zabor, Emily C.; Drill, Esther; Wang, Patricia I.; Nanjangud, Gouri J.; Redzematovic, Almedina; Nargund, Amrita M.; Manley, Brandon J.; Arcila, Maria E.; Donin, Nicholas M.; Cheville, John C.; Thompson, R. Houston; Pantuck, Allan J.; Russo, Paul; Cheng, Emily H.; Lee, William; Tickoo, Satish K.; Ostrovnaya, Irina; Creighton, Chad J.; Papaemmanuil, Elli; Seshan, Venkatraman E.; Hakimi, A. Ari and Hsieh, James J. (2017): Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma. In: Jci insight, Vol. 2, No. 12, e92688

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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.

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