title: Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma.
abstract: We previously showed that primary tumor-based orthotopic xenograft mouse models of medulloblastoma replicated the histopathological phenotypes of patients' original tumors. Here, we performed global gene expression profiling of 11 patient-specific xenograft models to further determine whether the xenograft tumors were molecularly accurate during serial subtransplantations in mouse brains and whether they represented all the molecular subtypes of medulloblastoma that were recently described. Analysis of the transcriptomes of 9 pairs of matched passage I xenografts and patients' tumors revealed high correlation coefficients (r(2) > 0.95 in 5 models, > 0.9 in 3 models, and > 0.85 in 1 model) and only identified 69 genes in which expressions were altered (FDR = 0.0023). Subsequent pair-wise comparisons between passage I, III, and V xenografts from the 11 models further showed that no dramatic alterations were introduced (r(2) > 0.9 in 8 models and > 0.8 in 3 models). The genetic abnormalities of each model were then identified through comparison with control RNAs from 5 normal cerebella and 2 fetal brains. Hierarchical clustering using 3 previously published molecular signatures showed that our models span the whole spectrum of molecular subtypes, including SHH (n = 2), WNT (n = 2), and the most recently identified group C (n = 4) and group D (n = 3). In conclusion, we demonstrated that the 11 orthotopic medulloblastoma xenograft models were molecularly faithful to the primary tumors, and our comprehensive collection of molecularly distinct animal models should serve as a valuable resource for the development of new targeted therapies for medulloblastoma.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Litian
authors.initials: L
authors.lastname: Yu
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Patricia
authors.initials: P
authors.lastname: Baxter
authors.forename: Horatiu
authors.initials: H
authors.lastname: Voicu
authors.forename: Sivashankarappa
authors.initials: S
authors.lastname: Gurusiddappa
authors.forename: Joseph
authors.initials: J
authors.lastname: Luan
authors.forename: Jack M
authors.initials: JM
authors.lastname: Su
authors.forename: Hon-chiu Eastwood
authors.initials: HC
authors.lastname: Leung
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse