title: Distal Chr 4 harbors a genetic locus (Gct1) fundamental for spontaneous ovarian granulosa cell tumorigenesis in a mouse model.
abstract: The spontaneous development of juvenile-onset ovarian granulosa cell tumors in mice of the SWXJ-9 recombinant inbred strain is a model for juvenile-type granulosa cell tumors that appear in very young girls. To expedite gene discovery in this mouse model of childhood cancer, we did a gene mapping study with the SWXJ-9 recombinant inbred strain and the evolutionarily divergent Mus musculus castaneus (CAST/Ei) strain as a mapping partner. Our mapping strategy focused on autosomal determinants of susceptibility with a backcross scheme that exploited a paternal, parent-of-origin effect for a X-linked gene (Gct4) that strongly supports granulosa cell tumor development. Of 1,968 backcross females examined, we detected 81 granulosa cell tumor-bearing animals and compared their allelic inheritance patterns to non-tumor-bearing siblings in a case-control analysis. The results of our study have confirmed an important locus on mouse chromosome (Chr) 4 (Gct1) and have revealed new loci for granulosa cell tumor susceptibility (Gct7-Gct9) on Chrs 1, 2, and 13 with susceptibility alleles contributed by the SWXJ-9 progenitor. Two novel gene-gene interactions supportive for granulosa cell tumor development were also observed between loci on Chrs 17 and 18 and loci on Chrs 2 and 10. Our data substantiate the evidence that Gct1 on Chr 4 is a fundamental oncogene for granulosa cell tumorigenesis in mice and has identified additional interacting autosomal loci that support tumor development.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA. amd@jax.org
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dorward
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Shultz
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Horton
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Beamer
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006106:Granulosa Cell Tumor / Q000235:genetics*; D007178:Inbreeding; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics*