Genetic variations in EGF and EGFR and glioblastoma outcome

Abstract

Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94–1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99–1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor.

Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

“…Egf is located on HAS 4 and over-expression of Egf has been associated with tumor progression and lower GBM survival [89]. Egf exhibited AEU and of the 24 exons analyzed, nine exons had significant associations with GBM survival.…”

Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas

“…These association studies are likely to identify new genes that play a role in the pathogenesis of glioblastomas, and will eventually contribute to a better understanding of the origin of the disease. We have recently shown an association between epidermal growth factor (EGF) polymorphisms and poor prognosis in patients with glioblastomas [22]. In addition, polymorphisms of LIG4, BTBD2, HMGA2 and RTEL1 genes involved in the double-strand break repair pathway have been associated with survival in glioblastomas [23].…”

Genetic and epigenetic contribution to astrocytic gliomas pathogenesis

“…; Sjöström et al . ). Meanwhile, EGFR VIII is concurrently expressed as a mutated receptor in 50% of glioblastomas with amplification of EGFR (Ekstrand et al .…”

“…1). The autocrine interaction of this receptor with its ligand can lead to increased cell proliferation (Agosti et al 1992;Hurt et al 1992;Sj€ ostr€ om et al 2010). Meanwhile, EGFR VIII is concurrently expressed as a mutated receptor in 50% of glioblastomas with amplification of EGFR (Ekstrand et al 1992;Aldape et al 2004;Mellinghoff et al 2005).…”