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EGFR
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Interpretation 121
Tier 2
EGFR
Variants
EGFR A289V
EGFR A289D
EGFR G598V
EGFR P596L
EGFR codon(s) 289, 596, 598 any
Primary Sites
Spinal Cord
Brain
Brain, Supratentorial
Brain, Infratentorial
Tumor Types
Glioblastoma
Interpretation

EGFR mutations in GBM cluster in the extracellular (EC) domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). In vitro and in vivo studies reveal anchorage-independent growth and tumorigenic potential when the A289 and G598 variants are stably expressed in NIH-3T3 cells. The A289 and G598 mutations sensitize Ba/F3 cells to erlotinib in vitro according to some reports, although other reports state glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). The A289 variant has been reported to show sensitivity towards BAY846, a tyrosine kinase inhibitor in brain tumors. In addition, according to some reports, inhibitors which bind to the inactive EGFR conformation potently inhibit EGFR EC mutants and induce cell death in EGFR mutant GBM cells.

Citations
  1. Longo et al. Bay846, a new irreversible small molecule inhibitor of EGFR and Her2, is highly effective against malignant brain tumor models. Invest New Drugs (2012) 30:2161–2172
  2. Vivanco I, Robins HI, Rohle D, et al. Differential Sensitivity of Glioma- versus Lung Cancer-specific EGFR mutations to EGFR Kinase Inhibitors. Cancer Discovery. 2012;2(5):458-471. doi:10.1158/2159-8290.CD-11-0284.
  3. Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O'Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, Mellinghoff IK. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med. 2006 Dec;3(12):e485. PubMed PMID: 17177598; PubMed Central PMCID: PMC1702556.
Last updated: 2015-12-09 20:15:19 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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