Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas

BACKGROUND: Malignant gliomas are the most prevalent type of primary brain tumours but the therapeutic armamentarium for these tumours is limited. Platelet-derived growth factor (PDGF) signalling has been shown to be a key regulator of glioma development. Clinical trials evaluating the efficacy of anti-PDGFRA therapies on gliomas are ongoing. In this study, we intended to analyse the expression of PDGFA and its receptor PDGFRA, as well as the underlying genetic (mutations and amplification) mechanisms driving their expression in a large series of human gliomas. METHODS: PDGFA and PDGFRA expression was evaluated by immunohistochemistry in a series of 160 gliomas of distinct World Health Organization (WHO) malignancy grade. PDGFRA-activating gene mutations (exons 12, 18 and 23) were assessed in a subset of 86 cases by PCR-single-strand conformational polymorphism (PCR-SSCP), followed by direct sequencing. PDGFRA gene amplification analysis was performed in 57 cases by quantitative real-time PCR (QPCR) and further validated in a subset of cases by chromogenic in situ hybridisation (CISH) and microarray-based comparative genomic hybridisation (aCGH). RESULTS: PDGFA and PDGFRA expression was found in 81.2% (130 out of 160) and 29.6% (48 out of 160) of gliomas, respectively. Its expression was significantly correlated with histological type of the tumours; however, no significant association between the expression of the ligand and its receptor was observed. The absence of PDGFA expression was significantly associated with the age of patients and with poor prognosis. Although PDGFRA gene-activating mutations were not found, PDGFRA gene amplification was observed in 21.1% (12 out of 57) of gliomas. No association was found between the presence of PDGFRA gene amplification and expression, excepting for grade II diffuse astrocytomas. CONCLUSION: The concurrent expression of PDGFA and PDGFRA in different subtypes of gliomas, reinforce the recognised significance of this signalling pathway in gliomas. PDGFRA gene amplification rather than gene mutation may be the underlying genetic mechanism driving PDGFRA overexpression in a portion of gliomas. Taken together, our results could provide in the future a molecular basis for PDGFRA-targeted therapies in gliomas

Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden

The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69–81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear

Early metabolic responses in temozolomide treated low-grade glioma patients

Amino acid transport and protein synthesis are important steps of tumor growth. We investigated the time course of tumor metabolism in low-grade gliomas (LGG) during temozolomide chemotherapy, and compared metabolic responses as measured with positron emission tomography (PET) with volume responses as revealed by magnetic resonance imaging (MR). A homogeneous population of 11 patients with progressive non-enhancing LGG was prospectively studied. Imaging was done at 6-months intervals starting six months, and in a second series starting three months after treatment initiation. F-18 fluoro-ethyl-l-tyrosine (FET) uptake was quantified with PET as metabolically active tumor volume, and was compared with the tumor volume on MR. Response was defined as ≥10% reduction of the initial tumor volume. Eight patients showed metabolic responses. Already 3 months after start of chemotherapy the active FET volumes decreased in 2 patients to a mean of 44% from baseline. First MR volume responses were noted at 6 months. Responders showed a volume reduction to 31 ± 23% (mean ± SD) from baseline for FET, and to 73 ± 26% for MR. The time to maximal volume reduction was 8.0 ± 4.4 months for FET, and 15.0 ± 3.0 months for MR. The initial metabolic response correlated with the best volume response on MR (Spearman Rank P = 0.011). Deactivation of amino acid transport represents an early indicator of chemotherapy response in LGG. Response assessment based on MR only has to be reconsidered. The time window obtained from PET may assist for individual treatment decisions in LGG patients