title: Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.
abstract: Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neurofibromas/malignant peripheral nerve sheath tumors were observed; however, a range of other tumor types was also observed. Our findings indicate that zebrafish mimic distinct features of the human disease and are complementary to mouse models.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Utrecht University, Utrecht, the Netherlands.
authors.forename: Harma
authors.initials: H
authors.lastname: Feitsma
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.forename: Jeroen
authors.initials: J
authors.lastname: Korving
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000008:Abdominal Neoplasms / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005134:Eye Neoplasms / Q000235:genetics; D005260:Female; D006394:Hemangiosarcoma / Q000235:genetics; D008297:Male; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000235:genetics*; D018317:Nerve Sheath Neoplasms / Q000235:genetics; D017253:Neurofibromatoses / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes