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Published on: January 22, 2013
Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic
Gabriel G Malouf1, Siraj M Ali2, Kai Wang2
1Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, Paris, France.
Background:
The genomic features underpinning renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) are not well understood, and at present, there are no specific or effective therapies for sRCC.
Objective:
To identify genomic alterations in patients with sRCC.
Design, Setting, And Participants:
We conducted genomic profiling on paired epithelial and sarcomatoid areas of three sRCC cases. Genomic profiling was performed on another 23 sRCC patients harboring diverse epithelial components (total of 26 cases). Genomic profiling was conducted using a hybrid capture DNA next-generation sequencing assay of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC (ccRCC) devoid of a sarcomatoid component, and with clear cell, papillary, and chromophobe renal cell carcinoma datasets from The Cancer Genome Atlas. Four additional ccRCC cases underwent whole exome sequencing.
Outcome Measurements And Statistical Analysis:
Genomic alterations in patients with sRCC and ccRCC were described, and their frequencies were compared using the Fisher exact test.
Results And Limitations:
Two of three patients with sRCC who underwent genomic profiling of both their epithelial and sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 26 sRCCs, TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Limitations include the small sample size.
Conclusions:
We found that sRCC contains different driver mutations than ccRCC. The epithelial and sarcomatoid components of sRCC largely contain the same genomic features. On the basis of harboring either TP53 or NF2 mutations, sRCC can be divided into two groups. These findings may have implications for understanding the oncogenesis of sarcomatoid renal tumors and for defining systemic treatment options.
Patient Summary:
Next-generation sequencing of tumors from patients with sarcomatoid kidney cancer reveals mutations that differ from those in nonsarcomatoid patients. These findings have implications in understanding the pathobiology of sarcomatoid kidney cancer and indicate the need for a different treatment approach in these patients.
Insights
Genomic profiling of sarcomatoid renal cell carcinoma (sRCC) reveals distinct driver mutations compared to clear cell RCC. These findings in sRCC, particularly TP53 and NF2 mutations, may guide future targeted therapies.
Area of Science:
- Genomic analysis of rare cancer subtypes.
- Oncogenesis and molecular pathology of renal cell carcinoma.
- Translational oncology and targeted therapy development.
Background:
- Genomic underpinnings of sarcomatoid renal cell carcinoma (sRCC) remain poorly understood.
- Current therapeutic options for sRCC are limited and lack specificity.
- Sarcomatoid dedifferentiation represents a high-risk subtype of renal cell carcinoma.
Purpose of the Study:
- To identify and characterize genomic alterations in patients diagnosed with sRCC.
- To compare the genomic landscape of sRCC with clear cell renal cell carcinoma (ccRCC).
- To explore potential therapeutic implications based on identified mutations.
Main Methods:
- Conducted hybrid capture DNA next-generation sequencing (NGS) on 26 sRCC cases, analyzing 236 cancer-related genes.
- Performed comparative genomic profiling against 56 ccRCC cases and public datasets (The Cancer Genome Atlas).
- Analyzed paired epithelial and sarcomatoid components from three sRCC cases for intra-tumor heterogeneity.
Main Results:
- Identical mutational profiles were observed in paired epithelial and sarcomatoid components in 2/3 sRCC cases.
- Frequent alterations in sRCC included TP53 (42.3%), VHL (34.6%), CDKN2A (26.9%), and NF2 (19.2%).
- NF2 mutations showed mutual exclusivity with TP53 mutations but not with VHL mutations.
Conclusions:
- sRCC harbors distinct driver mutations compared to ccRCC, suggesting different oncogenic pathways.
- sRCC can be molecularly sub-classified based on TP53 or NF2 mutation status.
- Identified genomic alterations provide a basis for understanding sRCC oncogenesis and developing targeted treatments.
