# Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma

## TL;DR

This study identifies a five-gene model based on hypoxia and glycolysis to predict kidney cancer outcomes and guide treatment choices.

## Contribution

A novel hypoxia–glycolysis-related gene prognostic model for kidney renal clear cell carcinoma is developed and validated.

## Key findings

- A five-gene model (ADORA2B, TGFA, FBP1, HK3, PDHB) effectively predicts clinical outcomes in KIRC.
- Low-risk patients show higher immunotherapy responsiveness and sensitivity to Gefitinib and Afatinib.
- High-risk patients exhibit elevated tumor mutational burden and sensitivity to Topotecan and Irinotecan.

## Abstract

Hypoxia and glycolysis play crucial roles in tumor progression, yet their association with kidney renal clear cell carcinoma (KIRC) remains unclear. Here, a novel prognostic model was developed with hypoxia–glycolysis-related genes (HGRGs) in KIRC, providing insights to elucidate the aforementioned uncertainties.

Transcriptomic information and clinical characteristics of KIRC were acquired from The Cancer Genome Atlas Program, ArrayExpress database, and Gene Expression Omnibus. Significant HGRGs were identified, and a prognostic model was constructed. We performed enrichment analysis, tumor mutational burden (TMB), tumor microenvironment), and drug sensitivity analyses to elucidate potential mechanisms of HGRGs.

The prognostic model based on five HGRGs (ADORA2B, TGFA, FBP1, HK3, PDHB) effectively predicted the clinical outcome. The nomogram, which integrates a prognostic model and clinical information, demonstrated superior performance. Low-risk patients were enriched in fatty acid metabolism and peroxisome pathways, exhibited higher immunotherapy responsiveness, and showed greater sensitivity to Gefitinib and Afatinib. High-risk patients exhibited activation of inflammatory and profibrotic pathways, an elevated TMB, immunosuppressive microenvironments, and greater sensitivity to Topotecan and Irinotecan. RT-qPCR validated the expression of HGRGs across selected cell lines.

The prognostic model derived from five HGRGs demonstrates excellent clinical value in predicting prognosis and guiding therapeutic strategies in KIRC.