Prevalence and prognosis of hypoxia-inducible factor-2α (HIF-2α) pathway gene mutations across advanced solid tumors

Abstract

Introduction: Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis.

Methods: This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types.

Results: Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations.

Discussion and conclusions: The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study.

Keywords: HIF‐2α; epidemiology; oncology; prevalence; prognosis.

FIGURE 1

Distribution of tumor types (A), prevalence of HIF‐2α gene mutations (B, C) and OS by HIF‐2α gene mutation status (D). (A) Distribution of 15 tumor types in the study population; (B) Prevalence of HIF‐2α gene mutations (by each individual gene) across the 15 tumor types; (C) Prevalence of HIF‐2α gene mutations (by each individual gene) in each of the 15 tumor types; (D) OS by HIF‐2α gene mutation status, adjusted for age, sex, race, practice type, and tumor type; CRC: colorectal cancer; HCC: hepatocellular cancer; MPM: mesothelioma.; NSCLC: non‐small cell lung cancer; RCC: renal cell cancer; SCLC: small cell lung cancer.