Details

Autor(en) / Beteiligte

• Sun, Guangxi
• Zhang, Xingming
• Liang, Jiayu
• Pan, Xiuyi
• Zhu, Sha
• Liu, Zhenhua
• Armstrong, Cameron M
• Chen, Jianhui
• Lin, Wei
• Liao, Banghua
• Lin, Tianhai
• Huang, Rui
• Zhang, Mengni
• Zheng, Linmao
• Yin, Xiaoxue
• Nie, Ling
• Shen, Pengfei
• Zhao, Jinge
• Zhang, Haoran
• Dai, Jindong
• Shen, Yali
• Li, Zhiping
• Liu, Jiyan
• Chen, Junru
• Liu, Jiandong
• Wang, Zhipeng
• Zhu, Xudong
• Ni, Yuchao
• Qin, Dan
• Yang, Ling
• Chen, Yuntian
• Wei, Qiang
• Li, Xiang
• Zhou, Qiao
• Huang, Haojie
• Yao, Jin
• Chen, Ni
• Zeng, Hao

Titel

Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma

Ist Teil von

• Clinical cancer research, 2021-03, Vol.27 (6), p.1734-1743

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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. 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. 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; = 0.03). These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.