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Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and potential therapeutic targets

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机构: [1]Sichuan Univ, West China Hosp, Sichuan Clin Res Ctr Kidney & Urol Dis, Dept Urol,Inst Urol, Chengdu, Peoples R China [2]Sichuan Univ, West China Hosp, Dept Pathol, Chengdu, Peoples R China [3]Army Med Univ, Southwest Hosp, Dept Urol, Chongqing, Peoples R China [4]Sichuan Univ, West China Hosp, Med Device Regulatory Res & Evaluat Ctr, Dept Urol, Chengdu, Peoples R China [5]Sichuan Univ, West China Hosp, Dept Radiol, Chengdu, Peoples R China [6]Univ Hosp Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland [7]Univ Zurich, Fac Med, CH-8006 Zurich, Switzerland [8]Peking Univ Canc Hosp & Inst, Dept Genitourinary Oncol, Key Lab Carcinogenesis & Translat Res, Minist Educ Beijing, Beijing, Peoples R China [9]Peking Univ First Hosp, Dept Urol, Beijing, Peoples R China [10]Kunming Med Univ, Affiliated Hosp 1, Dept Urol, Kunming, Peoples R China [11]First Peoples Hosp Neijiang, Dept Urol Surg, Neijiang, Peoples R China [12]Yaan Peoples Hosp, Dept Urol, Yaan, Peoples R China [13]Mianyang Cent Hosp, Dept Urol, Mianyang, Peoples R China [14]Kunming Med Univ, Affiliated Qujing Hosp, Ward Urol 2, Qujing, Peoples R China [15]Sichuan Univ, West China Hosp, Dept Nucl Med, Chengdu, Peoples R China [16]Sichuan Univ, West China Hosp, Dept Biotherapy, Chengdu, Peoples R China
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Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conduct a comprehensive integrated genomic study. We analyze the association of FH alteration patterns with tumor heterogeneity and develop a CpG site-specific methylation signature for precise identification of FH-deficient RCC. Transcriptomic analysis unveils three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derive the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 display moderate response to this therapeutic approach. In contrast, tumors in C3 exhibit an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.

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大类 | 1 区 综合性期刊
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Q1 MULTIDISCIPLINARY SCIENCES
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Q1 MULTIDISCIPLINARY SCIENCES

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第一作者机构: [1]Sichuan Univ, West China Hosp, Sichuan Clin Res Ctr Kidney & Urol Dis, Dept Urol,Inst Urol, Chengdu, Peoples R China
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