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.
基金:
Natural Science Foundation of China (NSFC) [82472673, 82103097, 82202901, 82203110, 82273047, 82172785, 81902577, 81974398, 81872107, 81872108]; China Postdoctoral Science Foundation [2021M692286, 2021M692281]; Research Foundation for the Postdoctoral Program of Sichuan University [2021SCU12014]; The 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYJC21020]; Science and Technology Support Program of Sichuan Province [2021YFS0119]; Natural Science Foundation of Sichuan Province [2023NSFSC1856, 2023NSFSC1857, 23NSFSC2454]; Post-Doctor Research Project, West China Hospital, Sichuan University [20HXBH026, 2021HXBH028]; CAMS Innovatinn Fund for Medical Sciences [2022-I2M-CT-B-098]