title: Genetic dissection of the Mss4 locus mediating sex-biased cancer resistance in the rat peripheral nervous system.
abstract: 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.
authors.affiliation: Department of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: van den Berg
authors.forename: Bernd U
authors.initials: BU
authors.lastname: Koelsch
authors.forename: Bettina
authors.initials: B
authors.lastname: Winzen-Reichert
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Andrea
authors.initials: A
authors.lastname: Kutritz
authors.forename: Andrea
authors.initials: A
authors.lastname: Kindler-Röhrborn
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D008297:Male; D051381:Rats; D012306:Risk; D012583:Schwann Cells / Q000473:pathology; D059467:Transcriptome / Q000235:genetics; D014276:Trigeminal Nerve / Q000473:pathology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C079550:Rabif protein, rat
keywords: estrogen receptor; malignant schwannoma; rodents; sex difference