High-resolution genetic map of X-linked juvenile-type granulosa cell tumor susceptibility genes in mouse.
SWR/Bm (SWR) female mice spontaneously develop early-onset ovarian granulosa cell (GC) tumors that can progress to metastatic carcinoma and thus provide a model system for human, juvenile-type GC tumors. In SWR mice, GC tumor susceptibility is an inherited, polygenic trait that appears at a low frequency. A dramatic increase in tumor frequency occurs when the autosomal SWR genetic complement is combined with the X-linked Gct4 allele of the mouse strain SJL/Bm (SJL). The modifier effect of the SJL Gct4 allele (Gct4(J)) also shows a strong parent-of-origin effect, occurring only when the Gct4(J) allele is paternally inherited. To genetically localize Gct4, we generated seven congenic mouse strains (SWR.SJL-X1 through -X7) that contained a defined segment of the SJL X chromosome (Chr) on the SWR autosomal strain background and mapped Gct4 to a 3 cM region. To better define the location of Gct4, we created an additional congenic strain (SWR.CAST-X) that contains most of the genetically polymorphic Chr X from the strain CAST/Ei. From crosses of the SWR.CAST-X and SWR.SJL-X congenic strains, we derived males carrying unique combinations of SJL-X and CAST-X segments. Progeny testing subsequently revealed a second SJL-derived, GC tumor frequency modifier gene, Gct6, located 6.5 cM distal to Gct4 on Chr X. In summary, we have mapped two modifier genes on the mouse Chr X that cause high-frequency, juvenile-type GC tumor development in female mice. The identity of these genes will provide a solid foundation for determination of tumor susceptibility genes in human cases of juvenile-type GC tumors.
Dorward
Ann M
AM
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Shultz
Kathryn L
KL
Ackert-Bicknell
Cheryl L
CL
Eicher
Eva M
EM
Beamer
Wesley G
WG
D000818:Animals; D002874:Chromosome Mapping / Q000379:methods; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006106:Granulosa Cell Tumor / Q000235:genetics*; D007178:Inbreeding; D008297:Male; D051379:Mice; D009857:Oncogenes / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D011995:Recombination, Genetic; D014960:X Chromosome / Q000235:genetics*