Impact ofEGFRGenetic Variants on Glioma Risk and Patient Outcome

Abstract

Background: The epidermal growth factor receptor (EGFR) regulates important cellular processes and is frequently implicated in human tumors. Three EGFR polymorphisms have been described as having a transcriptional regulatory function: two single-nucleotide polymorphisms in the essential promoter region, À216G/T and À191C/A, and a polymorphic (CA) n microsatellite sequence in intron 1. We aimed to elucidate the roles of these EGFR polymorphisms in glioma susceptibility and prognosis.Methods: We conducted a case-control study with 196 patients with glioma and 168 cancer-free controls. Unconditional multivariate logistic regression models were used to calculate ORs and 95% confidence intervals. A Cox regression model was used to evaluate associations with patient survival. False-positive report probabilities were also assessed.Results: None of the EGFR À216G/T variants was significantly associated with glioma risk. The À191C/A genotype was associated with higher risk for glioma when the (CA) n alleles were classified as short for 16 or 17 repeats. Independently of the (CA) n repeat cutoff point used, shorter (CA) n repeat variants were significantly associated with increased risk for glioma, particularly glioblastoma and oligodendroglioma. In all tested models with different (CA) n cutoff points, only À191C/A genotype was consistently associated with improved survival of patients with glioblastoma.Conclusions: Our findings implicate EGFR À191C/A and the (CA) n repeat polymorphisms as risk factors for gliomas, and suggest À191C/A as a prognostic marker in glioblastoma.Impact: Our data support a role of these EGFR polymorphisms in determining glioma susceptibility, with potential relevance for molecularly based stratification of patients with glioblastoma for individualized therapies. Cancer Epidemiol Biomarkers Prev; 20(12); 2610-7. Ó2011 AACR.

Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis

“…HOTAIR is a known oncogenic lncRNA in several tumor types (reviewed in [7,8]) including gliomas [15][16][17]. The roles of HOTAIR have been widely reported Fig.…”

“…Other putative causes may include familial aggregation, genetic syndromes, telomere maintenance and genetic polymorphisms [12][13][14]. The importance of inherited genetic variants in glioma risk has been highly addressed in both candidate-gene and genomewide association studies (GWAS) approaches, which revealed single nucleotide polymorphisms (SNPs) in cancer-related genes associated with glioma risk (e.g., TERT, EGF, EGFR, TGF-β1, CCDC26, CDKN2A/CDKN2B, PHLDB1 and RTEL1 [15][16][17][18]). …”

Dihydroartemisinin suppresses glioma proliferation and invasion via inhibition of the ADAM17 pathway

“…EGFR is the main tyrosine kinase receptor expressed in gliomas, and a high level of expression is correlated with tumor malignancy and unfavorable prognosis [24,25]. The EGFR transactivation mechanism requires the cleavage and shedding of membrane-bound EGFR ligands by ADAM17 [12,13,26].…”

Pharmacogenetics as Innovative Approach for Phase I Clinical Studies in Cancer Patients

“…Also genetic differences concerning drug target can explain differences in response or toxicity between individuals. The number of cytosine/adenine repeats in the intron 1 of epidermal growth factor receptor (EGFR), can affect the receptor activity and could potentially interfere with the activity of EGFR inhibitors as cetuximab [7].…”

“…Impaired glucuronidation activity of the UGT1A1 enzyme is a predisposing factor to severe irinotecan toxicity, due to a genetic polymorphism of the UGT1A1 gene. UGT1A1*28 is a TA indel polymorphism characterized by an extra TA repeated in the promoter region of the gene [A(TA) 7 TAA]. This polymorphism is thought to be associated with reduced glucuronidation of SN38, the active metabolite of irinotecan, compared with wild-type UGT1A1 [A(TA) 6 TAA], leading to variability in the PK of SN38 [4].…”