iPSC Modeling of Ovarian Cancers in BRCA1 and 2 Mutation Carriers

Project summary

Survival from a diagnosis of ovarian cancer continues to be significantly affected the usually late stage of disease diagnosis and the lack of clinical biomarkers to detect the disease at the earliest most treatable stages, then survival rates would likely increase and mortality rates decrease significantly. We hypothesize that the development and characterization of human avatars of fallopian tube epithelium (FTE) differentiated from induced pluripotent stem cell (iPSC) models of women carrying germline BRCA1/BRCA2 mutations can identify novel molecular mechanisms and biomarkers of early-stage pathogenesis for high grade serous ovarian cancers (HGSOCs). We further hypothesize that engineering these models with TP53 mutations will identify novel biomarkers for the diagnosis of HGSOC. We will model iPSC:FTE differentiation in women with BRCA1/BRCA2 mutations alone and in combination with TP53 mutation after using gene editing to make the mutation. We will validate the function of different combinations of mutations in the neoplastic progression of iPSC:FTEs. Single cell multiome profiling of RNA & protein will be used to establish the molecular mechanisms of FTE tissue heterogeneity. We expect to identify high probability neoplastic biomarkers based on unique cell types of FTEs and will use proteomic strategies to validate these biomarkers in a unique biorepository of ~60,000 serum/plasma specimens from more than 1,300 high risk women with and without BRCA1/BRCA2 mutations.

This grant was made possible in part by a generous donation from the Mike & Patti Hennessy Foundation.