Genetic Variations of Kinase Inserts Domain Receptor (KDR) Gene Are Associated with the Risk of Astrocytomas

Gao, Yufei; Ma, Piyong; He, Yichun; Liu, Yan; Jiang, Yang

doi:10.1007/s12035-015-9239-6

Cited by 10 publications

(14 citation statements)

References 54 publications

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“…Moreover, Q472H mutation was found to increase KDR protein phosphorylation and associated with MVD in non-small cell lung cancer [ 33 ]. However, this mutation in astrocytomas showed a protective effect [ 34 ]. In ES, it has been shown that VEGF plays an important role in angiogenesis and tumorigenesis, but the mechanism involving its receptors is not clear [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Heterogeneity of Ewing Sarcoma as Detected by Ion Torrent Sequencing

et al. 2016

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Ewing sarcoma (ES) is the second most common malignant bone and soft tissue tumor in children and adolescents. Despite advances in comprehensive treatment, patients with ES metastases still suffer poor outcomes, thus, emphasizing the need for detailed genetic profiles of ES patients to identify suitable molecular biomarkers for improved prognosis and development of effective and targeted therapies. In this study, the next generation sequencing Ion AmpliSeq™ Cancer Hotspot Panel v2 was used to identify cancer-related gene mutations in the tissue samples from 20 ES patients. This platform targeted 207 amplicons of 2800 loci in 50 cancer-related genes. Among the 20 tissue specimens, 62 nonsynonymous hotspot mutations were identified in 26 cancer-related genes, revealing the molecular heterogeneity of ES. Among these, five novel mutations in cancer-related genes (KDR, STK11, MLH1, KRAS, and PTPN11) were detected in ES, and these mutations were confirmed with traditional Sanger sequencing. ES patients with KDR, STK11, and MLH1 mutations had higher Ki-67 proliferation indices than the ES patients lacking such mutations. Notably, more than half of the ES patients harbored one or two possible ‘druggable’ mutations that have been previously linked to a clinical cancer treatment option. Our results provided the foundation to not only elucidate possible mechanisms involved in ES pathogenesis but also indicated the utility of Ion Torrent sequencing as a sensitive and cost-effective tool to screen key oncogenes and tumor suppressors in order to develop personalized therapy for ES patients.

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Section: Discussionmentioning

confidence: 99%

Molecular Heterogeneity of Ewing Sarcoma as Detected by Ion Torrent Sequencing

et al. 2016

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“…Despite the frequent presence of the variant in our patient cohort the allele frequency did not significantly differ from the general population suggesting a limited impact on oncogenesis. 32,33 However, the KDR (kinase insert domain receptor, also known as VEGFR2) Q472H variant has been associated with an angiogenic phenotype characterized by increased tumor vascular density and VEGF secretion. Studies on melanoma cells harboring KDR Q472H demonstrated higher proliferative and invasive capacity and sensitivity to targeted inhibition of VGFR2.…”

Section: Discussionmentioning

confidence: 99%

Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets

et al. 2017

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Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated. Mutational analysis demonstrated mutations in TP53, PTEN, FGFR3, CDKN2A, and RB1. TP53 mutations were seen in 11 (44%) of patients and detected in myxofibrosarcomas G1, G3, with heterogeneous morphology and G3 with subsequent metastases in 1 patient (16%), 3 patients (42%), 2 patients (62.5%), and 3 patients (75%), respectively. Additional mutations were detected in 2 patients, intratumoral mutational heterogeneity in 1 patient. We observed a variety of copy number alterations typical for myxofibrosarcomas, with higher numbers in G3 compared with G1 myxofibrosarcomas. Cluster analysis revealed distinctive features especially in metastatic and recurrent disease. Focal alterations affected CDKN2A, CCND1, CCNE1, EGFR, EPHA3, EPHB1, FGFR1, JUN, NF1, RB1, RET, TP53, and additional novel amplifications in CCNE1, KIT, EGFR, RET, BRAF, NTRK2 were seen in G3 compared with the G1 tumor areas. The total number of focal events in G1 versus G3 tumors differed significantly (P=0.0014). TRIO and RICTOR co-amplification was seen in 8 (44%) G3 and 1 (10%) G1 myxofibrosarcomas and RICTOR amplification alone in 4 (40%) G1 myxofibrosarcomas. TRIO amplification was significantly (P=0.0218) higher in G3 myxofibrosarcomas indicating a late genetic event. These findings support the use of expanded molecular profiling in myxofibrosarcomas to detect drug-able targets to allow patients to participate in basket trials.

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“…Some gene polymorphisms are functional and can affect the expression or structure of a protein [41,42]. In the VEGF and VEGFR2 genes, we focused on four functional VEGF polymorphisms (2549 I/D, rs1570360 G/A, rs2010963 C/G, and rs3025039 C/T) and two functional VEGFR2 polymorphisms (rs2071559 C/T and rs1870377 A/T), which may affect angiogenesis-related diseases [43][44][45][46][47][48][49][50][51].…”

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confidence: 99%

“…The rs1870377 A/T polymorphism changes the sequence of the amino acids from His (T allele) to Gln (A allele), and the T allele shows higher binding affinity of VEGF to VEGFR2 [50]. This allele is also associated with susceptibility to astrocytomas [51].…”

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confidence: 99%

Gene polymorphisms of <i>VEGF</i> and <i>VEGFR2</i> are associated with the severity of Hashimoto’s disease and the intractability of Graves’ disease, respectively

et al. 2020

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Vascular endothelial growth factor (VEGF) is one of main regulators of angiogenesis that functions by binding to its receptors, including VEGF receptor (VEGFR) 2. There are few data available regarding the association between VEGF and VEGFR polymorphisms and the susceptibility to and prognosis of autoimmune thyroid diseases (AITDs). To elucidate this association, we genotyped four functional VEGF and two VEGFR2 polymorphisms and measured serum VEGF levels. In the four functional VEGF polymorphisms, the frequencies of the I carrier and I allele of VEGF -2549 I/D, which has lower activity, were higher in patients with severe HD than in those with mild HD. In the two functional VEGFR2 polymorphisms, the frequency of the rs2071559 CC genotype, which has higher activity, was higher in patients with intractable GD than in controls, and the proportion of GD patients with larger goiters was higher in those with the CC genotype. Moreover, the frequency of the rs1870377 TT genotype with higher activity was higher in patients with intractable GD than in those with GD in remission. Combinations of VEGF and VEGFR2 polymorphisms with stronger interactions were associated with the intractability of GD. Serum VEGF levels were higher in HD and AITD patients than those in controls. In conclusion, VEGF polymorphisms with lower activity were associated with the severity of HD, while VEGFR2 polymorphisms and the combinations of VEGF and VEGFR2 polymorphisms, which have stronger interactions, were associated with the intractability of GD. VEGF and VEGFR2 polymorphisms were associated with HD severity and GD intractability, respectively.

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Genetic Variations of Kinase Inserts Domain Receptor (KDR) Gene Are Associated with the Risk of Astrocytomas

Cited by 10 publications

References 54 publications

Molecular Heterogeneity of Ewing Sarcoma as Detected by Ion Torrent Sequencing

Molecular Heterogeneity of Ewing Sarcoma as Detected by Ion Torrent Sequencing

Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets

Gene polymorphisms of <i>VEGF</i> and <i>VEGFR2</i> are associated with the severity of Hashimoto’s disease and the intractability of Graves’ disease, respectively

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