RGD Reference Report - Genetic dissection of the Mss4 locus mediating sex-biased cancer resistance in the rat peripheral nervous system. - Rat Genome Database

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Genetic dissection of the Mss4 locus mediating sex-biased cancer resistance in the rat peripheral nervous system.

Authors: Van den Berg, L  Koelsch, BU  Winzen-Reichert, B  Fischer, C  Kutritz, A  Kindler-Rohrborn, A 
Citation: van den Berg L, etal., Int J Cancer. 2015 May 1;136(9):2099-108. doi: 10.1002/ijc.29256. Epub 2014 Oct 28.
RGD ID: 11566050
Pubmed: (View Article at PubMed) PMID:25303613
DOI: Full-text: DOI:10.1002/ijc.29256

The incidence of neural tumors is sexually dimorphic in both, humans and rodents. The identification of genetic determinants contributing to sex-biased tumor development is an essential prerequisite for differential tumor prevention in males and females. F2 hybrids of inbred BDIV and BDIX rats, resistant and susceptible, respectively, to ethylnitrosourea-induced malignant peripheral nerve sheath tumors (MPNST) display a marked sex bias regarding tumor risk. Homozygous BDIV alleles at the Mss4 locus (90.9-111.2 Mb, chromosome 6) mediate MPNST resistance exclusively in female F2 rats according to a genome wide association analysis. This locus was functionally confirmed and fine mapped through MPNST induction in males and females of three congenic rat strains (BDIX.BDIV-Mss4a, b, d). As a consequence, it could be subdivided in Mss4.1 (98.8-99.7 Mb) mediating cancer resistance, and Mss4.2 (99.7-111.2 Mb) enhancing sex specificity. Positional candidate genes were selected through DNA sequencing and expression profiling using RNAs from trigeminal nerve tissue of parental and congenic male and female animals. The transregulatory fingerprint of BDIV or BDIX alleles at Mss4.1 and/or Mss4.2, respectively, provided insight into the processes influencing cancer risk in a sex-biased way. A group of genes, a fraction of which involved in Schwann cell differentiation, showed low, male-biased expression in nerve tissues under the control of BDIX susceptibility alleles, but high, female-biased transcript levels when controlled by BDIV resistance alleles at Mss4. The Esr2 gene located in Mss4.1 constitutes an interesting functional candidate together with a yet unidentified gene/enhancer in Mss4.2.

Annotation

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Objects Annotated

QTLs
Schws8  (Schwannoma susceptibility QTL 8)
Schws9  (Schwannoma susceptibility QTL 9)

Objects referenced in this article
Strain BDIX.BDIV-D6Mit1-D6Mgh2/Zte null Rattus norvegicus
Strain BDIX.BDIV-D6Mit8-D6Rat229/Zte null Rattus norvegicus
Strain BDIX.BDIV-D6Rat132-D6Mgh3/Zte null Rattus norvegicus
Strain BDIX.BDIV-D6Rat132-D6Rat229/Zte null Rattus norvegicus

Additional Information