Fine map of the Gct1 spontaneous ovarian granulosa cell tumor locus

• Published in: Mammalian genome 2013-02, Vol.24 (1-2), p.63-71
• Main Authors: Smith, Kerri N, Halfyard, Sarah J, Yaskowiak, Edward S, Shultz, Kathryn L, Beamer, Wesley G, Dorward, Ann M
• Format: Article
• Language: English
• Subjects: Alleles; Androgens; Animal Genetics and Genomics; animal ovaries; Animals; Biomedical and Life Sciences; carcinogenesis; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Cycle Proteins; Cell Line, Tumor; Cell Transformation, Neoplastic - chemically induced; Chromosome Mapping; Dehydroepiandrosterone - pharmacology; Disease Models, Animal; Disease Susceptibility; Female; females; Genetic Loci; Genotype; girls; Granulosa Cell Tumor - genetics; Granulosa Cell Tumor - pathology; homozygosity; Human Genetics; Humans; infants; Life Sciences; loci; Mice; Mice, Inbred Strains; neoplasms; Phenotype; prasterone; Testosterone - metabolism
• ISSN: 0938-8990; 1432-1777
• DOI: 10.1007/s00335-012-9439-6

The spontaneous development of juvenile-onset, ovarian granulosa cell (GC) tumors in the SWR/Bm (SWR) inbred mouse strain is a model for juvenile-type GC tumors that appear in infants and young girls. GC tumor susceptibility is supported by multiple Granulosa cell tumor (Gct) loci, but the Gct1 locus on Chr 4 derived from SWR strain background is fundamental for GC tumor development and uniquely responsive to the androgenic precursor dehydroepiandrosterone (DHEA). To resolve the location of Gct1 independently from other susceptibility loci, Gct1 was isolated in a congenic strain that replaces the distal segment of Chr 4 in SWR mice with a 47 × 10⁶-bp genomic segment from the Castaneus/Ei (CAST) strain. SWR females homozygous for the CAST donor segment were confirmed to be resistant to DHEA- and testosterone-induced GC tumorigenesis, indicating successful exchange of CAST alleles (Gct1 Cᴬ ) for SWR alleles (Gct1 Sᵂ ) at this tumor susceptibility locus. A series of nested, overlapping, congenic sublines was created to fine-map Gct1 based on GC tumor susceptibility under the influence of pubertal DHEA treatment. Twelve informative lines have resolved the Gct1 locus to a 1.31 × 10⁶-bp interval on mouse Chr 4, a region orthologous to human Chr 1p36.22.