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Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

¹ Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center and ² Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, the Netherlands

Requests for reprints: Edwin Cuppen, Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Phone: 31-30-2121969; Fax: 31-30-2516554; E-mail: e.cuppen{at}niob.knaw.nl.

Key Words: zebrafish • mismatch repair • cancer • neurofibroma • microsatellite instability

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. [Cancer Res 2008;68(13):5059–66]

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