The Validation of a Precursor Lesion of Epithelial Ovarian Cancer in Fancd2-KO Mice

SIMPLE SUMMARY: The advancement of improved early detection is in part hampered by limited knowledge of ovarian cancer (OC) origin, difficulties in accessing early-stage OC in female patients and a lack of animal models to study early OC development. The Fancd2 knock-out (KO) animal model has formerly been shown to develop epithelial ovarian cancer, with the purported precursor lesion hypothesised to develop from primordial ovarian follicles prematurely devoid of their germ cell. This hypothesis was based on our extensive knowledge of follicle development and qualitative observation. Therefore, for the first time, we sought to demonstrate a relationship between the proposed precursor cells and a late-stage tumour using gene expression analysis, providing genetic evidence to support the use of this animal model as a novel tool to study early epithelial ovarian cancer. ABSTRACT: Ovarian cancer (OC) has the highest mortality rate of all gynaecological malignancies. The asymptomatic nature and limited understanding of early disease hamper research into early-stage OC. Therefore, there is an urgent need for models of early-stage OC to be characterised to improve the understanding of early neoplastic transformations. This study sought to validate a unique mouse model for early OC development. The homozygous Fanconi anaemia complementation group D2 knock-out mice (Fancd2(−/−)) develop multiple ovarian tumour phenotypes in a sequential manner as they age. Using immunohistochemistry, our group previously identified purported initiating precursor cells, termed ‘sex cords’, that are hypothesised to progress into epithelial OC in this model. To validate this hypothesis, the sex cords, tubulostromal adenomas and equivalent controls were isolated using laser capture microdissection for downstream multiplexed gene expression analyses using the Genome Lab GeXP Genetic Analysis System. Principal component analysis and unbiased hierarchical clustering of the resultant expression data from approximately 90 OC-related genes determined that cells from the sex cords and late-stage tumours clustered together, confirming the identity of the precursor lesion in this model. This study, therefore, provides a novel model for the investigation of initiating neoplastic events that can accelerate progress in understanding early OC.