Landscape of genomic alterations in genes implicated in the regulation of hypoxia inducible factor (HIF) signaling: A pooled analysis of two pan-cancer cohorts.

Abstract

3143 Background: HIF2 alpha inhibitors (HIF2i) have been recently approved for VHL-related tumors, especially clear cell renal cell carcinoma (ccRCC). Alterations in genes that regulate HIF signaling may modulate response to HIF2i and may help identify tumor types that could benefit from new therapeutic approaches targeting HIF activity. Here, we describe the landscape of these alterations across different cancer types. Methods: This study included patients (pts) from the TCGA PanCancer Atlas and GENIE Cohort v17.0, across all cancer types. All pts underwent Next Generation Sequencing or OncoPanel analysis of their tumors. Alterations in genes related to the HIF pathway ( VHL , EPAS1 , EGLN1 , and EGLN2 ) and citric acid cycle ( SDHA , SDHB , SDHC , SDHD , SDHAF1 , FH , IDH1 , IDH2 , and MDH2 ) were screened, and only driver mutations, identified by OncoKB, CIViC Variants, My Cancer Genome, and the available literature, were included. Pts with a mutation in at least one gene were included. Mutation frequencies across different cancer types were analyzed for each cohort, then pooled together. Results: We identified a total of 10,953 and 167,073 pts on TCGA and GENIE, respectively. Mutation frequencies for different cancer types are shown in the Table. Among the mutated cases, IDH1 was the most altered gene in glioma (90.20% [95% Confidence Interval (CI): 90.19; 90.21]), hepatobiliary cancers (75.48% [75.40; 75.56]) and melanoma (55.75% [55.57; 55.92]), and the second most common in leukemia (39.86% [39.68; 40.04]), while IDH2 was the most altered in leukemia (57.52% [57.34; 57.70]), and the second most common in glioma (5.25% [5.24; 5.25]), and hepatobiliary cancers (19.10% [19.04; 19.17]). SDHA was the second most altered gene in melanoma (12.95% [12.87; 13.03]). In RCC, VHL was the most mutated gene (92.79% [92.78; 92.79]), followed by FH (2.41% [2.40; 2.41]). EPAS1 was mutated in 64.19% of cases with driver mutations in miscellaneous neuroepithelial tumors (MNET) ([57.07; 71.31]), but not in RCC. Among the altered cases in pheochromocytoma, SDHB was the most commonly altered gene (39.71% [35.31; 44.11], followed by VHL (18.41% [15.92; 20.91]). SDHB was also the second most common gene to be mutated in MNET (23.12% [19.37; 26.86]). Conclusions: In this analysis, mutations in HIF-regulating genes were detected in multiple cancers, and were not limited to those studied in the context of HIF inhibitors. Further research is required to elucidate whether these gene alterations sensitize tumors to HIF inhibition. Pooled mutation frequencies for all considered genes in different cancer types. Cancer Type N % Pooled Mutation Frequency of any gene 95% CI RCC 3662 39.76 39.74; 39.77 Glioma 12657 23.67 23.67; 23.67 Leukemia 1857 15.49 15.47; 15.50 Hepatobiliary Cancer 4234 11.18 11.18; 11.19 MNET 253 8.61 8.54; 8.68 Pheochromocytoma 198 5.63 5.56; 5.69 Melanoma 6589 4.34 4.34; 4.34