Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma
Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma
复制标题
富马酸水合酶缺陷型肾细胞癌的综合分子表征
DOI：
10.1158/1078-0432.ccr-20-3788
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发表时间：
2021-03-15
影响因子：
11.5
通讯作者：
Zeng, Hao
中科院分区：
文献类型：
--
作者：
Sun, Guangxi;Zhang, Xingming;Zeng, Hao
目的：富马酸水合酶缺陷型肾细胞癌（FH缺陷型RCC）是一种罕见但致命的肾癌亚型。对FH缺陷型RCC的基因组特征知之甚少，晚期疾病的治疗选择有限。为此，我们进行了一项全面的基因组学研究，以表征FH缺陷RCCs.Experimental Design的基因组和表观基因组特征：综合基因组，表观基因组和分子分析进行了25个未经处理的主要FH缺陷RCC。完整的临床病理和随访数据，这些患者recorded.Results：我们发现，FH缺陷型肾癌表现出低体细胞突变负担（中位数0.58突变每兆碱基），但频繁的体细胞拷贝数改变。大多数FH缺陷型RCC的特征是CpG位点岛甲基化表型，在转录因子、肿瘤抑制因子和肿瘤标志通路的基因中的许多CpG位点显示协同的超甲基化。然而，少数低转移潜能的病例（20%）显示相对较低的DNA甲基化水平，表明FH缺陷型RCC中甲基化模式的异质性。此外，FH缺陷型RCC具有潜在的高度免疫原性，其特征在于肿瘤T细胞浸润增加，但肿瘤中免疫检查点分子的高表达。临床数据进一步表明，接受免疫检查点阻断为基础的治疗的患者实现了改善与抗血管生成单药治疗的无进展生存（中位数，13.3与5.1个月; P = 0.03）。结论：这些结果揭示了基因组特征，并提供了新的见解FH缺陷RCC的潜在治疗策略。
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.