TY - JOUR
T1 - Integrated molecular characterization of fumarate hydratase deficient renal cell carcinoma
AU - Sun, Guangxi
AU - Zhang, Xingming
AU - Liang, Jiayu
AU - Pan, Xiuyi
AU - Zhu, Sha
AU - Liu, Zhenhua
AU - Armstrong, Cameron M.
AU - Chen, Jianhui
AU - Lin, Wei
AU - Liao, Banghua
AU - Lin, Tianhai
AU - Huang, Rui
AU - Zhang, Mengni
AU - Zheng, Linmao
AU - Yin, Xiaoxue
AU - Nie, Ling
AU - Shen, Pengfei
AU - Zhao, Jinge
AU - Zhang, Haoran
AU - Dai, Jindong
AU - Shen, Yali
AU - Li, Zhiping
AU - Liu, Jiyan
AU - Chen, Junru
AU - Liu, Jiandong
AU - Wang, Zhipeng
AU - Zhu, Xudong
AU - Ni, Yuchao
AU - Qin, Dan
AU - Yang, Ling
AU - Chen, Yuntian
AU - Wei, Qiang
AU - Li, Xiang
AU - Zhou, Qiao
AU - Huang, Haojie
AU - Yao, Jin
AU - Chen, Ni
AU - Zeng, Hao
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - 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 FHdeficient 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 FHdeficient RCC.
AB - 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 FHdeficient 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 FHdeficient RCC.
UR - http://www.scopus.com/inward/record.url?scp=85104386974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104386974&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-3788
DO - 10.1158/1078-0432.CCR-20-3788
M3 - Article
AN - SCOPUS:85104386974
SN - 1078-0432
VL - 27
SP - 1734
EP - 1743
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -