Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

Rand, Vikki; Huang, Jiaqi; Stockwell, Tim; Ferriera, Steve; Buzko, Oleksandr; Lévy, Samuel; Busam, Dana; Li, Kelvin; Edwards, Jennifer B.; Eberhart, Charles G.; Murphy, Kathleen M.; Tsiamouri, Alexia; Beeson, Karen; Simpson, Andrew J.G.; Venter, J. Craig; Riggins, Gregory J.; Strausberg, Robert L.

doi:10.1073/pnas.0507200102

Cited by 138 publications

(99 citation statements)

References 50 publications

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“…One possible explanation for double mutations is that only one mutation is functional. This is supported in part by the observation that the only double mutation sample from our study was found to exhibit lowlevel microsatellite instability (22). The mismatch repair instability within these tumors increases not only the chances of point mutations that activate oncogenes or inactivate tumor suppressors but also the background mutation rate in these genomes.…”

Section: Discussionsupporting

confidence: 69%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

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151

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The phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that relay important cellular growth control signals. Recently, a large-scale mutational analysis of eight PI3K and eight PI3K-like genes revealed somatic mutations in PIK3CA, which encodes the p110A catalytic subunit of class IA PI3K, in several types of cancer, including glioblastoma multiforme. In that report, 4 of 15 (27%) glioblastomas contained potentially oncogenic PIK3CA mutations. Subsequent studies, however, showed a significantly lower mutation rate ranging from 0% to 7%. Given this disparity and to address the relation of patient age to mutation frequency, we examined 10 exons of PIK3CA in 73 glioblastoma samples by PCR amplification followed by direct DNA sequencing. Overall, PIK3CA mutations were found in 11 (15%) samples, including several novel mutations. PIK3CA mutations were distributed in all sample types, with 18%, 9%, and 13% of primary tumors, xenografts, and cell lines containing mutations, respectively. Of the primary tumors, PIK3CA mutations were identified in 21% and 17% of pediatric and adult samples, respectively. No evidence of PIK3CA gene amplification was detected by quantitative real-time PCR in any of the samples. This study confirms that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in glioblastomas is of value.Moreover, this is the first study showing PIK3CA mutations in pediatric glioblastomas, thus providing a molecular target in this important pediatric malignancy.

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Section: Discussionsupporting

confidence: 69%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

Self Cite

151

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“…Kinome exon sequencing in search of human cancer somatic mutations identifi ed FGF signaling components as the most frequently mutated coding regions among protein kinases ( 14 ). Somatic mutations of FGFR1 have been found in gliomas and lung tumors ( 15,16 ), of FGFR2 in gastric RESEARCH ARTICLE and endometrial carcinomas (17)(18)(19), of FGFR3 in bladder carcinomas and multiple myeloma ( 20,21 ), and of FGFR4 in primary rhabdomyosarcomas ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

et al. 2012

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Patient stratifi cation biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identifi cation of patient stratifi cation biomarkers for NVP-BGJ398, a novel and selective fi broblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the fi rst time, we report oncogenic FGFR1 amplifi cation in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our fi ndings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identifi ed predictors of sensitivity. SIGNIFICANCE:The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefi t the most from any given drug. To this end, we have integrated the molecular profi les for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specifi c patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118-33.

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“…Activating mutations in PDGFRa are common in gastro-intestinal stromal (GIST) tumors 18,19 and deletions of PDGFRa have been identified in gliomas and glioblastomas. 20,21 Hypereosinophilic syndrome (OMIM 607685) can result from fusion of the PDGFRa and FIP1L1 genes. 22 The role of PDGFRa gene in human neural tube defects (NTD) has also been examined, but the association between high-expressing and low-expressing PDGFRa promoter haplotypes and NTD remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

Bleyl

Moshrefi

Shaw³

et al. 2007

Eur J Hum Genet

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Congenital diaphragmatic hernia (CDH) is a common, life threatening birth defect. Although there is strong evidence implicating genetic factors in its pathogenesis, few causative genes have been identified, and in isolated CDH, only one de novo, nonsense mutation has been reported in FOG2 in a female with posterior diaphragmatic eventration. We report here that the homozygous null mouse for the Pdgfra gene has posterolateral diaphragmatic defects and thus is a model for human CDH. We hypothesized that mutations in this gene could cause human CDH. We sequenced PDGFRa and FOG2 in 96 patients with CDH, of which 53 had isolated CDH (55.2%), 36 had CDH and additional anomalies (37.5%), and 7 had CDH and known chromosome aberrations (7.3%). For FOG2, we identified novel sequence alterations predicting p.M703L and p.T843A in two patients with isolated CDH that were absent in 526 and 564 control chromosomes respectively. These altered amino acids were highly conserved. However, due to the lack of available parental DNA samples we were not able to determine if the sequence alterations were de novo. For PDGFRa, we found a single variant predicting p.L967V in a patient with CDH and multiple anomalies that was absent in 768 control chromosomes. This patient also had one cell with trisomy 15 on skin fibroblast culture, a finding of uncertain significance. Although our study identified sequence variants in FOG2 and PDGFRa, we have not definitively established the variants as mutations and we found no evidence that CDH commonly results from mutations in these genes.

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Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

Cited by 138 publications

References 50 publications

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

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