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.
Simon Gayther, PhD, received his postgraduate degree in Cancer Genetics from University College London (UCL) in the UK. He undertook his postgraduate training at Cambridge University, UK, before returning to UCL as Faculty in 2004. He moved to the USA in 2010, first to the University of Southern California as Full Professor and then to Cedars Sinai Medical Center in 2015 where he is currently Professor in the Department of Biomedical Sciences, Director of Molecular Epidemiology, Director of the Center for Bioinformatics and Functional Genomics and Co-Director of the Applied Genomics, Computational and Translational Core. Throughout his career, his laboratory work has focused on cancer genetics and understanding the function of genetic risk alleles that cause ovarian and breast cancers. His research has been funded by the Medical Research Council (MRC) and Cancer Research UK (CRUK) in the UK, and by the NIH, the Department of Defense, Ovarian Cancer Research Alliance, and other cancer foundations in the USA
Dr. Gayther’s research has primarily focused on understanding the genetic events associated with risk, initiation and development of ovarian and breast cancers. Initially his work focused on the the highly penetrant BRCA1 and BRCA2 genes and their role in familial ovarian and breast cancers, which led to studies to identify additional genetic risk factors for ovarian cancer in the population, including the BRCA complex of genes using targeted sequencing approaches and common low penetrance risk alleles using genome wide association studies. Tying all of this together have been studies to characterize function and novel mechanisms underlying high, moderate and low risk alleles in the development of ovarian and breast cancers, specifically in vitro cell modeling of different protein coding risk variants, and epigenomic and transcriptomic modeling of non-coding risk alleles. Dr Gayther is principal investigator on several population based efforts to discover additional risk alleles for both ovarian and breast cancer and to establish their functional role in carcinogenesis. His overall goal is to reduce the burden of ovarian and breast cancer in the population by integrating omics methods for the identification of genetic risk factors with effective prevention strategies.