Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data.

Sang Y Lee,Bo Zhang,James R Connor,Dajiang J Liu,Sara T Langan,Anna C Salzberg,Junjia Zhu,Joshua E Muscat,Scott M Langevin

doi:10.1371/journal.pone.0174778

Abstract

Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119–0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474–0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients’ survival in the TCGA data set of GBM.

Highlights

Uptake of iron is regulated by several proteins including HFE, the hemochromatosis protein
We studied whether there is an association between HFE polymorphisms and survival of The Cancer Genome Atlas (TCGA) glioblastoma multiforme (GBM) patients; and, if so, whether that association is dependent on gender and/or HFE gene expression level
To determine which single nucleotide variation (SNV) were altered in GBM, we evaluated the frequency of SNVs in NB in TCGA GBM; and, we compared that frequency with the frequency in 1000Genome

Summary

Introduction

Uptake of iron is regulated by several proteins including HFE, the hemochromatosis protein. Polymorphisms in the HFE gene are relatively common in Caucasians with the frequency for H63D HFE heterozygote and homozygote around 22–28% (22–24% heterozygote and 2.4–4% homozygote) and for C282Y HFE heterozygote and homozygote about 9–10% (8–10% heterozygote and 0.4–1% homozygote) [2,3,4]. Both HFE polymorphisms are associated with increased cellular iron uptake [5,6,7] which may indicate an increased need for iron for cancer cell proliferation. In cell culture, both neuroblastoma and a number of astrocytoma cell lines show evidence of Temodar (chemotherapy standard of care) and radiation resistance [17]

Methods

Results

Conclusion