HIF family transcription factor expression in a cohort of 4362 patients with renal cell carcinoma (RCC).

4543 Background: The HIF pathway drives RCC pathogenesis operating through transcription factors (TFs) that function as heterodimers of the oxygen-sensitive α (HIF1α or HIF2α) and constitutively expressed β subunits (HIF1β or HIF2β). Loss of VHL leads to HIFα stabilization, nuclear translocation, and formation of transcriptional complexes with β subunits. We aimed to characterize the molecular and clinical features associated of HIF TF mRNA expression in RCC. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on RCC specimens (n = 4362) at Caris Life Sciences. HIF-High/Low expression was defined as > 75 th / < 25 th quartile RNA transcripts per million (TPM). Overall survival (OS) was defined as the time of diagnosis to death/last follow-up. Time on treatment (TOT) was defined as the time from treatment start to discontinuation. Results: The majority of patients were male (71%), of white race (61%), with median age of 64 years. HIF2α was lower in tumors from Black vs White patients (102.3 vs 157.5 TPM, p < 0.0001) and higher in tumors from Hispanic vs non-Hispanic White patients (146.1 vs 195.4 TPM, p < 0.01). Compared to kidney primary (n = 1,784, 43.9%, 172.1 TPM), HIF2α expression was lower in lymph nodes (n = 319, 7.9%, 97.6 TPM, p < 0.01) but similar to distant metastatic sites (n = 1,959, 48.2%, 168.3 TPM). Compared to clear cell RCC (n = 1198, 29.5%, 224.3 TPM), HIF2α expression was lower in papillary (n = 238, 5.9%, 57.5 TPM), chromophobe (n = 83, 2.0%, 91.7 TPM), and medullary RCC (n = 15, 0.36%, 46.5 TPM) (p < 0.01 each). Sarcomatoid RCC (n = 119, 2.9%) had lower HIF2α (111.9 vs. 155.0 TPM, p < 0.05), lower HIF2β (5.6 vs 8.5 TPM, p < 0.01), and higher HIF1α (276.3 vs 197.4 TPM, p < 0.01) compared to non-sarcomatoid RCC (n = 3947, 97.2%). Compared to VHL wild-type (n = 1415, 34.9%), VHL -mutated tumors (n = 1884, 46.4%) had higher HIF2α (206.6 vs 97.7 TPM), lower HIF1α (184.9 vs 233.9 TPM), lower HIF2β (7.2 vs 10.2 TPM) (p < 0.01 each). Tumors with high HIF2α were enriched for VHL , PBRM1 , MTOR , and PTEN alterations and had fewer TP53 , BAP1 , MET , SMARCB1 , and NF2 alterations. HIF1α-high tumors had fewer VHL , TSC1 , and BAP1 alterations . HIF1β -high tumors had decreased TP53 and RB1 and increased CHEK2 and PALB2 alterations. High HIF2α and HIF2β was associated with improved OS (92.6 vs 68.1 months, p < 0.001 and 87.4 vs 69.8 months, p < 0.004, respectively), while HIF1α and HIF1β did not correlate with OS. Patients with high HIF2α had prolonged cabozantinib TOT ( 8.1 vs 3.9 months, p < 0.001). Conclusions: This comprehensive analysis revealed distinct HIF TF expression patterns across RCC subgroups. Notably, elevated HIF2α expression was observed in clear cell RCC, VHL-mutated tumors, and was linked to improved OS and prolonged TOT with cabozantinib, suggesting a potential prognostic role for HIF2α in RCC, warranting further clinical investigation.