Chromosome X loci and spontaneous granulosa cell tumor development in SWR mice

Abstract

Females of the SWR/Bm (SWR) inbred mouse strain possess a unique susceptibility to juvenile-onset tumors originating from the granulosa cells (GC) of the ovarian follicles. Tumor susceptibility is an inherited, polygenic trait in SWR females, minimally involving an oncogenic Granulosa cell tumor susceptibility (Gct) locus on chromosome (Chr) 4 (Gct1), and two GC tumor susceptibility modifier genes mapped to distinct regions of Chr X (Gct4 and Gct6). Shifts in the frequency of GC tumor initiation in the SWR female population from low penetrance to moderate penetrance, or phenotype switching between GC tumor-susceptible and GC tumor-resistant, is strongly influenced by the allelic contributions at Gct4 and Gct6. In addition to the allele-specific effects, GC tumor susceptibility is controlled by the mode of X-linked transmission with a dominant, paternal parent-of-origin effect. We took advantage of the robust paternal effect with a recombinant male progeny testing strategy to resolve the Gct4 locus interval to 1.345 million base (Mb) pairs. Based on the mapping resolution and the phenotype sensitivity to endogenous and exogenous androgen exposure, a promising candidate for Gct4 identity is the androgen receptor (Ar) gene. We explored the mechanism of allelic variation for Ar between SWR (low penetrance allele) and SJL/Bm (SJL) (moderate penetrance allele) using an SWR.SJL-X congenic strain resource and a quantitative gene expression method. We report the low GC tumor penetrance allele of the SWR strain correlates with significantly reduced Ar transcript levels in the female ovary at the pubertal transition.

Keywords: :

• granulosa cell tumor
• tumor susceptibility allele
• parent-of-origin effect

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was performed across two institutions, The Jackson Laboratory (TJL) and Memorial University of Newfoundland (MUN). The founder congenic line SWR.CAST-X development, reciprocal matings and male progeny testing at TJL was supported by NIH HD049397 (A.M.D.) and NCI Cancer Core Grant CA34196 (W.G.B.). Other experiments were performed at MUN, supported by Canada Foundation for Innovation, the Canada Research Chairs program and the Faculty of Medicine (A.M.D.). K.N.S. received fellowship support from the Faculty of Medicine and School of Graduate Studies (MUN) and a CIHR Masters award. The authors would like to acknowledge the assistance of the Computational Sciences group at TJL for custom SSLP primer design and the insightful contributions of Dr Eva Eicher throughout this project.

Supplemental Materials

Supplemental materials may be found here: www.landesbioscience.com/journals/epigenetics/article/23399