Purpose: Epidermal growth factor (EGF) plays a critical role in cancer. A polymorphism in the EGF gene (EGF+61) may influence its expression and contribute to cancer predisposition and aggressiveness. In the present study, we aimed to elucidate the role of EGF+61in glioma susceptibility and prognosis. Experimental Design: A case-control study involving197 glioma patients and 570 controls was done. Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). False-positive report probability was also assessed. The luciferase reporter gene assay was used to ascertain the functional consequences of this polymorphism. Results: Corroborating the univariate analysis, the multivariate model showed that the G allele conferred higher risks for gliomas (OR, 1.32; 95% CI, 1.04-1.67), glioblastomas (OR, 1.47; 95% CI, 1.02-2.10), and oligodendrogliomas (OR, 1.55; 95% CI, 1.07-2.23). The GG genotypes were associated with increased risk for gliomas (OR, 1.71; 95% CI, 1.07-2.73), glioblastomas (OR, 2.03; 95% CI, 1.02-4.05), and oligodendrogliomas (OR, 2.72; 95% CI, 1.18-6.28). In addition, the AG+GG genotypes were associated with higher risk for gliomas (OR, 1.52; 95% CI, 1.03-2.23) and oligodendrogliomas (OR, 2.80; 95% CI, 1.35-5.79). No significant association was observed between the EGF+61polymorphism and glioblastoma or oligodendroglioma patients' overall survival. The luciferase reporter gene assay exhibited a significant increased promoter activity for the G variant compared with the reference A allele. Conclusions: These findings support the role of the EGF+61 polymorphism as a susceptibility factor for development of gliomas and show its implication on EGF promoter activity.

Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma.

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the a2-chain of laminin. We report two patients with partial laminin-a2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).

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.