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

Martinho, Olga; Longatto‐Filho, Adhemar; Lambros, MB; Martins, Albino; Pinheiro, Céline; Silva, A.; Pardal, Fernando; Amorim, Júlia; Mackay, Alan; Milanezi, Fernanda; Tamber, Narinder; Fenwick, Kerry; Ashworth, Alan; Reis‐Filho, JS; Lopes, José Manuel; Reis, Rui Manuel

doi:10.1038/sj.bjc.6605225

Cited by 108 publications

(87 citation statements)

References 66 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DNA was obtained from FFPE tissue sections representative of the tumor lesions using the QIAamp® DNA Micro Kit (Qiagen), following manufacturer's instructions and as previously described [17].…”

Section: Dna Isolation From Fppe Tissuementioning

confidence: 99%

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

et al. 2015

View full text Add to dashboard Cite

The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at −245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.

show abstract

Section: Dna Isolation From Fppe Tissuementioning

confidence: 99%

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The LNZ308, LN319, LN443, LN444, and SNB19 glioma cell lines endogenously expressed PDGFRα at moderate to high levels, whereas U87, U251, U373, T98G, LN18, and LN235 glioma cells had lower-level expression of PDGFRα ( Figure 1A). To correlate expression levels of PDGFRα proteins with PDGFRA gene status in these glioma cells, we performed quantitative PCR analyses (16). Consistent with the levels of PDGFRα protein, increased copy numbers of the PDGFRA gene were found in LNZ308, LN319, LN443, LN444, and SNB19 glioma cells.…”

Section: Dock180 Mediates Pdgfrα-stimulated Glioma Cell Migration Andmentioning

confidence: 99%

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Feng¹,

Hu²,

Liu³

et al. 2011

J. Clin. Invest.

105

109

View full text Add to dashboard Cite

Two hallmarks of glioblastoma multiforme, the most common malignant brain cancer in humans, are aggressive growth and the ability of single glioma cells to disperse throughout the brain. These characteristics render tumors resistant to current therapies and account for the poor prognosis of patients. Although it is known that oncogenic signaling caused by overexpression of genes such as PDGFRA is responsible for robust glioma growth and cell infiltration, the mechanisms underlying glioblastoma malignancy remain largely elusive. Here, we report that PDGFRα signaling in glioblastomas leads to Src-dependent phosphorylation of the guanine nucleotide exchange factor Dock180 at tyrosine 1811 (Dock180 Y1811 ) that results in activation of the GTPase Rac1 and subsequent cell growth and invasion. In human glioma cells, knockdown of Dock180 and reversion with an RNAi-resistant Dock180 Y1811F abrogated, whereas an RNAi-resistant Dock180 WT rescued, PDGFRα-promoted glioma growth, survival, and invasion. Phosphorylation of Dock180 Y1811 enhanced its association with CrkII and p130 Cas , causing activation of Rac1 and consequent cell motility. Dock180 also associated with PDGFRα to promote cell migration. Finally, phosphorylated Dock180 Y1811 was detected in clinical samples of gliomas and various types of human cancers, and coexpression of phosphorylated Dock180 Y1811 , phosphorylated Src Y418 , and PDGFRα was predictive of extremely poor prognosis of patients with gliomas. Taken together, our findings provide insight into PDGFRα-stimulated gliomagenesis and suggest that phosphorylated Dock180 Y1811 contributes to activation of Rac1 in human cancers with PDGFRA amplification.

show abstract

“…Reference DNA was obtained from lymphocytes from a total of four healthy volunteers. q-PCR was performed in triplicate using each PDGFRA and 18S gene-specific primer set as described previously (Martinho et al 2009), reagents, and protocols from Applied Biosystems in a 7900 HT Fast Real-Time PCR System. The PCR amplification was performed in a 10-mL reaction volume under the following conditions: 23 Power SYBR Green PCR Master Mix (Applied Biosystems), 0.5 mM primers, and 20 ng of DNA.…”

Section: Glioma Specimensmentioning

confidence: 99%

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

et al. 2010

View full text Add to dashboard Cite

Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-a (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA D8, 9 , an intragenic deletion rearrangement. The PDGFRA D8, 9 mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.[Keywords: Copy number alteration; glioma; PDGFRA gene rearrangement; receptor tyrosine kinase] Supplemental material is available at http://www.genesdev.org.

show abstract

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

Cited by 108 publications

References 66 publications

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

Contact Info

Product

Resources

About