title: Evolutionary etiology of high-grade astrocytomas.
abstract: Glioblastoma (GBM), the most common brain malignancy, remains fatal with no effective treatment. Analyses of common aberrations in GBM suggest major regulatory pathways associated with disease etiology. However, 90% of GBMs are diagnosed at an advanced stage (primary GBMs), providing no access to early disease stages for assessing disease progression events. As such, both understanding of disease mechanisms and the development of biomarkers and therapeutics for effective disease management are limited. Here, we describe an adult-inducible astrocyte-specific system in genetically engineered mice that queries causation in disease evolution of regulatory networks perturbed in human GBM. Events yielding disease, both engineered and spontaneous, indicate ordered grade-specific perturbations that yield high-grade astrocytomas (anaplastic astrocytomas and GBMs). Impaired retinoblastoma protein RB tumor suppression yields grade II histopathology. Additional activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) network drives progression to grade III disease, and further inactivation of phosphatase and tensin homolog (PTEN) yields GBM. Spontaneous missense mutation of tumor suppressor Trp53 arises subsequent to KRAS activation, but before grade III progression. The stochastic appearance of mutations identical to those observed in humans, particularly the same spectrum of p53 amino acid changes, supports the validity of engineered lesions and the ensuing interpretations of etiology. Absence of isocitrate dehydrogenase 1 (IDH1) mutation, asymptomatic low grade disease, and rapid emergence of GBM combined with a mesenchymal transcriptome signature reflect characteristics of primary GBM and provide insight into causal relationships.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Song
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Burak
authors.initials: B
authors.lastname: Kutlu
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
authors.forename: Ryan
authors.initials: R
authors.lastname: Bash
authors.forename: Debra
authors.initials: D
authors.lastname: Gilbert
authors.forename: Chaoying
authors.initials: C
authors.lastname: Yin
authors.forename: T Norene
authors.initials: TN
authors.lastname: O'Sullivan
authors.forename: Chunyu
authors.initials: C
authors.lastname: Yang
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bullitt
authors.forename: Ken D
authors.initials: KD
authors.lastname: McCarthy
authors.forename: Tal
authors.initials: T
authors.lastname: Kafri
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000209:etiology*; D001483:Base Sequence; D005075:Biological Evolution; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D005818:Genetic Engineering / Q000379:methods*; D005909:Glioblastoma / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: cancer initiation; cancer progression; mouse model preclinical