title: Preservation of KIT genotype in a novel pair of patient-derived orthotopic xenograft mouse models of metastatic pediatric CNS germinoma.
abstract: Metastatic intracranial germinoma is difficult to treat. Although the proto-oncogene KIT is recognized as one of the most frequent genetic abnormalities in CNS germinoma, the development of new target therapeutic agents for CNS germinoma is hampered by the lack of clinically-relevant animal models that replicate the mutated or over-expressed KIT. CNS germinoma tumor cells from five pediatric patients were directly implanted into the brains of Rag2/severe combined immune deficiency mice. Once established, the xenograft tumors were sub-transplanted in vivo in mouse brains. Characterization of xenograft tumors were performed through histologic and immunohistochemical staining, and KIT mutation analysed with quantitative pyro-sequencing. Expression of putative cancer stem cell markers (CD133, CD15, CD24, CD44, CD49f) was analyzed through flow cytometry. Two patient-derived orthotopic xenograft (PDOX) models (IC-6999GCT and IC-9302GCT) were established from metastatic germinoma and serially sub-transplanted five times in mouse brains. Similar to the original patient tumors, they both exhibited faint expression (+) of PLAP, no expression (-) of β-HCG and strong (+++) expression of KIT. KIT mutation (D816H), however, was only found in IC-9320GCT. This mutation was maintained during the five in vivo tumor passages with an increased mutant allele frequency compared to the patient tumor. Expression of putative cancer stem cell markers CD49f and CD15 was also detected in a small population of tumor cells in both models. This new pair of PDOX models replicated the key biological features of pediatric intracranial germinoma and should facilitate the biological and pre-clinical studies for metastatic intracranial germinomas.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Lindsay
authors.affiliation: Department of Neurosurgery, The 1st Affiliated Hospital, Soochow University, Suzhou, Jiangsu, 215007, People's Republic of China.
authors.forename: Yulun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Braun
authors.affiliation: Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Wan Yee
authors.initials: WY
authors.lastname: Teo
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Sibo
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Baxter
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Su
authors.affiliation: Children's Cancer Center, National Center for Child Health and Development, 2-10-1 Okura Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Terashima
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Perlaky
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Chintagumpala
authors.affiliation: Department of Pathology, Baylor College of Medicine/Texas Children's Hospital, 6621 Fannin Street, Houston, TX, 77030, USA.
authors.forename: Adekunle
authors.initials: A
authors.lastname: Adesina
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA.
authors.forename: D
authors.initials: D
authors.lastname: Williams Parsons
authors.affiliation: Department of Pediatrics, Baylor College of Medicine/Texas Children's Cancer Center, 1102 Bates, Suite 1030.07, Houston, TX, 77030, USA. xxli@txch.org.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D018237:Germinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit
keywords: Germinoma; KIT; Mouse models; Pediatric; Xenograft