Mutation analysis of B-RAF gene in human gliomas

Basto, Diana; Trovisco, Vítor; Lopes, José Manuel; Martins, Albino; Pardal, Fernando; Soares, Paula; Reis, Rui Manuel

doi:10.1007/s00401-004-0936-x

Cited by 81 publications

(67 citation statements)

References 16 publications

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“…Cancer patients' genomic DNA was extracted from formalin-fixed, paraffin-embedded tumor tissue, as previously described (24). No peripheral blood DNA was available from the majority of glioma patients.…”

Section: Methodsmentioning

confidence: 99%

Association between Functional EGF+61 Polymorphism and Glioma Risk

Costa

Ferreira

Costa

et al. 2007

Clinical Cancer Research

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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.

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Section: Methodsmentioning

confidence: 99%

Association between Functional EGF+61 Polymorphism and Glioma Risk

Costa

Ferreira

Costa

et al. 2007

Clinical Cancer Research

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“…In addition, oncogenic activation by point mutations, translocations, or inversions has been observed in about 60% of malignant melanomas, 50% of thyroid carcinomas, and 15% of colorectal and ovarian cancers (21,(31)(32)(33)(34)(35). In adult gliomas, previous studies have detected BRAF mutations in a small fraction of glioblastomas (36,37), and an individual case of oligodendroglioma has been reported (38). In addition, rare cases of gliomas were found to carry mutations in NRAS (36,38), while large copy number gains involving genes of the MAPK pathway were detected by chromosomal CGH analysis in 38 of 87 gliomas (44%) investigated (38).…”

Section: Mapk Signaling In Cancer the Ras/raf (Mapk) Signaling Cascadementioning

confidence: 99%

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

et al. 2008

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The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

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“…Raf are linked to a wide range of cancers including melanoma, colorectal, and glioma malignancies (Basto et al, 2005;Poynter et al, 2006;Barault et al, 2008). The conventional gene-disruption of B-Raf in mice revealed an unexpected function in vascular development.…”

Section: Dominant-activating Mutations In B-mentioning

confidence: 99%