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Published on: January 22, 2013
Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma
Guangxi Sun1, Xingming Zhang1, Jiayu Liang1
1Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
Purpose:
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.
Experimental Design:
Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.
Results:
We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).
Conclusions:
These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.
Insights
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) has a low mutation rate but frequent copy-number alterations. FH-deficient RCC is immunogenic, and immune checkpoint blockade improves patient outcomes.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and aggressive subtype of kidney cancer.
- Limited knowledge exists regarding its genomic profile and effective treatments for advanced stages.
Purpose of the Study:
- To comprehensively characterize the genomic and epigenomic features of FH-deficient RCC.
- To identify potential therapeutic strategies for this rare cancer subtype.
Main Methods:
- Integrated genomic, epigenomic, and molecular analyses of 25 untreated primary FH-deficient RCCs.
- Clinicopathologic and follow-up data collection for all patients.
Main Results:
- FH-deficient RCC exhibits low somatic mutation burden but frequent copy-number alterations.
- Most cases display a CpG island methylator phenotype, with notable heterogeneity.
- The tumors are potentially immunogenic, with increased T-cell infiltration and high immune checkpoint molecule expression.
- Immune checkpoint blockade showed improved progression-free survival compared to antiangiogenic monotherapy (13.3 vs. 5.1 months, P=0.03).
Conclusions:
- This study reveals key genomic and epigenomic features of FH-deficient RCC.
- Findings offer new insights into potential therapeutic avenues, particularly immunotherapy, for FH-deficient RCC patients.
