MPTH-20ALTERATIONS IN THE IRON REGULATORY GENE SIGNATURE ARE ASSOCIATED WITH DECREASED SURVIVAL IN LOW GRADE GLIOMA

Abstract

BACKGROUND: Iron is a tightly regulated micronutrient that is necessary for cell division in normal tissue. Previous studies have established that a signature of iron regulatory genes can predict survival in breast tumors. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in brain cancer pathophysiology. METHODS: We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with low grade brain gliomas (LGG). Specifically, we utilized the Coxnet package to perform feature selection using elastic net regularization and compared this model to the 1-Nearest Neighbor algorithm and random selection. To prevent overfitting in our Coxnet model, 10-fold cross-validation was implemented. RESULTS: Using feature reduction strategies we identified a novel, optimized subset of 10 iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, SLC25A37, ALAD, SLC25A28, TFR2, and HIF1AN) whose differential expression defines two phenotypic groups with differential survival of 62.9 months (94.5 vs 31.6 months, p< 10−6). The correlation between predicted relative risks and survival on the Coxnet model was -0.27, compared to a 0.30 correlation for the 1NN algorithm performed on all 61 iron regulatory genes. Therefore, feature selection eliminated 51 of the candidate genes with only a slight reduction in accuracy. CONCLUSIONS: This work indicates that iron metabolism affects tumor progression in multiple types, promising broader applicability for therapeutic and predictive strategies focusing on iron metabolism. The genes identified in this study are risk factors in other cancers, suggesting that targeting these genes could provide therapeutic and prognostic tools with utility beyond low grade glioma.