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Distal Chr 4 Harbors a Genetic Locus (Gct1) Fundamental for Spontaneous Ovarian Granulosa Cell Tumorigenesis in a Mouse Model

The Jackson Laboratory, Bar Harbor, Maine

Requests for reprints: Ann M. Dorward, The Jackson Laboratory, Box 202, 600 Main Street, Bar Harbor, ME 04609. Phone: 207-288-6216; Fax: 207-288-6073; E-mail: amd{at}jax.org.

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.

Key Words: ovarian cancer • granulosa cell tumor • mouse chromosome 4

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				A. M Dorward, K. L Shultz, and W. G Beamer LH analog and dietary isoflavones support ovarian granulosa cell tumor development in a spontaneous mouse model Endocr. Relat. Cancer, June 1, 2007; 14(2): 369 - 379. [Abstract] [Full Text] [PDF]