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Published on: February 22, 2015
Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas
Vikki Rand1, Jiaqi Huang, Tim Stockwell
1Department of Neurosurgery, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224, USA.
Abstract:
It is now clear that tyrosine kinases represent attractive targets for therapeutic intervention in cancer. Recent advances in DNA sequencing technology now provide the opportunity to survey mutational changes in cancer in a high-throughput and comprehensive manner. Here we report on the sequence analysis of members of the receptor tyrosine kinase (RTK) gene family in the genomes of glioblastoma brain tumors. Previous studies have identified a number of molecular alterations in glioblastoma, including amplification of the RTK epidermal growth factor receptor. We have identified mutations in two other RTKs: (i) fibroblast growth receptor 1, including the first mutations in the kinase domain in this gene observed in any cancer, and (ii) a frameshift mutation in the platelet-derived growth factor receptor-alpha gene. Fibroblast growth receptor 1, platelet-derived growth factor receptor-alpha, and epidermal growth factor receptor are all potential entry points to the phosphatidylinositol 3-kinase and mitogen-activated protein kinase intracellular signaling pathways already known to be important for neoplasia. Our results demonstrate the utility of applying DNA sequencing technology to systematically assess the coding sequence of genes within cancer genomes.
Insights
Researchers identified new mutations in fibroblast growth receptor 1 and platelet-derived growth factor receptor-alpha genes in glioblastoma. These receptor tyrosine kinases (RTKs) are key targets for cancer therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Tyrosine kinases are crucial targets for cancer therapeutics.
- Glioblastoma multiforme (GBM) exhibits various molecular alterations, including epidermal growth factor receptor (EGFR) amplification.
- High-throughput DNA sequencing enables comprehensive cancer genome analysis.
Purpose of the Study:
- To investigate mutations within the receptor tyrosine kinase (RTK) gene family in glioblastoma genomes.
- To identify novel RTK alterations beyond EGFR in GBM.
- To assess the role of identified RTK mutations in cancer signaling pathways.
Main Methods:
- Whole-genome sequencing of glioblastoma tumors.
- Sequence analysis of RTK gene family members.
- Identification and characterization of gene mutations.
Main Results:
- Identified mutations in fibroblast growth factor receptor 1 (FGFR1), including novel kinase domain mutations in cancer.
- Discovered a frameshift mutation in platelet-derived growth factor receptor-alpha (PDGFRA).
- FGFR1, PDGFRA, and EGFR mutations provide potential links to PI3K and MAPK signaling pathways.
Conclusions:
- DNA sequencing is a powerful tool for systematically analyzing cancer genomes.
- Mutations in FGFR1 and PDGFRA represent new therapeutic targets in glioblastoma.
- Understanding RTK alterations deepens insights into glioblastoma pathogenesis and therapeutic strategies.
