Grant: Master's Award: Canada Graduate Scholarships

Juvenile-type granulosa cell tumours, or JGCTs, are a subtype of ovarian cancer that appears before the onset of puberty in girls as young as one year of age. As in other pediatric cancers, the impact of environmental factors on risk is limited, indicating a genetic influence on susceptibility. Due to the rarity of these tumours, very little is known about the role of genetics in JGCT development. To ameliorate the lack of samples from the human population, a mouse model system has been developed using female mice of the SWR inbred strain which spontaneously develop JGCTs that mimic human tumours in both age of onset and hormonal profile. One percent of SWR mice will develop tumours, but the trait is unique to this particular strain, indicating that a genetic variant specific to the SWR genome influences the susceptibility of JGCT development. The number of SWR mice that develop tumours dramatically increases to 20% when the mice are implanted with androgen-releasing capsules, increasing trait penetrance and allowing for a genetic investigation to determine the gene responsible for JGCT susceptibility. A second inbred mouse strain, CAST, is resistant to JGCT development even under androgen treatment. By breeding SWR and CAST mice to produce sublines of offspring with variable segments of the two genomes, we are able to map the recombinant genome based on the development of tumours. This will allow us to narrow down the precise location of the gene responsible for cancer susceptibility within the Gct1 locus, an area of the SWR genome shown to influence JGCT development. The identification of the tumour susceptibility gene active in the mouse model will provide specific gene candidates for further investigation in human cases of pediatric granulosa cell tumours. The ultimate goal of this research is to shed light on the etiological basis of a disease with major consequences on the fertility of those affected, and for which such information is severely lacking.