Multi-omics Analyses and Molecular Subtypes to Provide Potential Therapeutic Implications in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

4522 Background: 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 conducted a comprehensive integrated genomic study. Methods: A total of 126 treatment naïve FH-deficient RCC tissue samples were extracted from our multi-center database. Whole-exome, RNA-seq, and DNA-methylation sequencing were performed. All cases were confirmed with both FH/2SC immunohistochemical staining and FH alterations analysis. Results: Through whole-exome sequencing, we found FH alteration patterns were associated with both tumor behavior and patient survival outcomes. Tumors harboring FH truncating alteration (including nonsense, frameshift and splice site mutations) and mutations near hinge regions (such as p.S419L), were predominantly associated with more aggressive tumor behavior and poorer prognosis. We further developed a CpG sites-specific methylation signature for precise identification of FH-deficient RCC. More importantly, transcriptomic analysis unveiled 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 derived the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 displayed moderate response to this therapeutic approach. In contrast, tumors in C3 exhibited an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. Conclusions: 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.