A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

Rene Garza, Robert A. Hudson, C. Alex McMahan, Christi A Walter, Kristine S Vogel

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

Original languageEnglish (US)
Pages (from-to)98-110
Number of pages13
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume615
Issue number1-2
DOIs
StatePublished - Feb 3 2007

Fingerprint

Neurofibromatosis 1
Phenotype
Neoplasms
DNA Repair
Genomic Instability
Neurilemmoma
Mutation
Plexiform Neurofibroma
Apoptosis
Genes
Loss of Heterozygosity
Brain
Heterozygote
Transgenes
Peripheral Nerves
DNA Damage
Disease Progression
Spleen
Liver
DNA

Keywords

  • Big Blue mouse
  • Mutant frequency
  • Neurofibromatosis type 1
  • p53
  • Peripheral nerve sheath tumor

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1. / Garza, Rene; Hudson, Robert A.; McMahan, C. Alex; Walter, Christi A; Vogel, Kristine S.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 615, No. 1-2, 03.02.2007, p. 98-110.

Research output: Contribution to journalArticle

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