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Genetic basis of sex-specific resistance to neuro-oncogenesis in (BDIX × BDIV) F2 rats

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Abstract

The identification of cancer susceptibility- and resistance-mediating genes is an essential prerequisite for prevention and early diagnosis of malignant tumors. Model organisms are helpful to identify variant alleles involved in pathways affecting individual cancer risk. BDIX and BDIV rats of both sexes are highly susceptible and resistant, respectively, to the development of N-ethyl-N-nitrosourea (ENU)-induced malignant peripheral nerve sheath tumors (MPNST), predominantly in the trigeminal nerves. Nevertheless, female (BDIV × BDIX) F2 intercross rats have a lower MPNST incidence and a longer latency time than males. Six of seven autosomal gene loci (Mss1-Mss7) controlling genetic susceptibility and resistance in (BDIV × BDIX) F2 hybrids exert allele- and sex-specific effects on tumor incidence and/or latency time of variable strength. Homozygous BDIV alleles at Mss4 or Mss7 located on rat chromosomes 6 and 10, respectively, are sufficient to cause almost complete resistance to ENU-induced MPNST development in female F2 rats regardless of the genotype of the other locus. Both loci display only weak effects on male cancer risk. Survival curves of ENU-treated F2 females depleted of animals with homozygous BDIV alleles at Mss4 and Mss7 are not significantly different from those of males, suggesting that these loci account mainly for the excess tumor resistance observed in female F2 rats. By haplotype analysis Mss4 and Mss7 could be narrowed down to 20 and 12 Mb, respectively, providing a basis for the positional identification of candidate genes.

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Acknowledgments

This work was supported by the Wilhelm Sander Stiftung, Munich, Germany (Grant 2005, 093.1 to AKR) and the Bonfor-Program (University of Bonn Research Council, Bonn, Germany). The authors thank Hans Ullrich Klatt, Institute of Neuropathology, University of Bonn Medical School, for help with the artwork and Thomas Haberland and Michael Oepp, Institute of Cell Biology (Cancer Research), University Hospital of Essen, University of Duisburg-Essen, for expert assistance with animal husbandry.

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Authors and Affiliations

  1. Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Bettina Winzen

  2. Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Bernd Koelsch & Andrea Kindler-Röhrborn

  3. Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Christine Fischer

Authors
  1. Bettina Winzen
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  2. Bernd Koelsch
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  3. Christine Fischer
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  4. Andrea Kindler-Röhrborn
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Corresponding author

Correspondence to Andrea Kindler-Röhrborn.

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B. Winzen and B. Koelsch contributed equally to this work.

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Winzen, B., Koelsch, B., Fischer, C. et al. Genetic basis of sex-specific resistance to neuro-oncogenesis in (BDIX × BDIV) F2 rats. Mamm Genome 20, 741–748 (2009). https://doi.org/10.1007/s00335-009-9226-1

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  • DOI: https://doi.org/10.1007/s00335-009-9226-1

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