Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.

H. Feitsma; R.V. Kuiper; J. Korving; I.J. Nijman; E. Cuppen

doi:10.1158/0008-5472.CAN-08-0019

Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.

H. Feitsma, R.V. Kuiper, J. Korving, I.J. Nijman, E. Cuppen

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

51 Citations (Scopus)

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 cafe-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.

Original language	English
Pages (from-to)	5059-5066
Journal	Cancer Research
Volume	68
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-08-0019
Publication status	Published - 2008

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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 cafe-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.",

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T1 - Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.

AU - Feitsma, H.

AU - Kuiper, R.V.

AU - Korving, J.

AU - Nijman, I.J.

AU - Cuppen, E.

N1 - Reporting year: 2008

PY - 2008

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N2 - 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 cafe-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.

AB - 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 cafe-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.

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DO - 10.1158/0008-5472.CAN-08-0019

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VL - 68

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JO - Cancer Research

JF - Cancer Research

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Zebrafish with mutations in mismatch repair genes develop neurofibromas and other tumors.

Abstract

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