Primary ovarian insufficiency (POI) is the most extreme form of infertility with loss of oocytes before the age of 40 years. We have made significant progress understanding the genetics of POI, with a candidate gene identified in 23-30% of women with POI after whole exome sequencing (WES). We demonstrated approximately 50% of gene variants are found in genes critical for DNA damage and repair and transcription/translation fidelity. These gene families are also implicated in cancer risk. Using genealogy information from the Utah Population Database (UPDB), we demonstrated that women with POI have increased relative risk for breast cancer, while their first-, second- and third-degree relatives have increased risk for breast, colon, and prostate cancer. We will use three generation families and additional validated cases of POI, gene identification decision support tools and functional models, along with replication cohorts to expand our studies for an in-depth examination of the relationship between POI and cancer risk. We will add clinical and basic science cancer and computational investigators and new artificial intelligence and genetic approaches to understand cancer risk in POI. Specific Aim 1 will identify additional cancer risk tracking with POI in affected women and their families using the UPDB and unique cancer clustering algorithms. Specific Aim 2 will identify genetic mutations in women with familial cancer risk through whole genome sequencing. We will use novel software (GEM) developed at the University of Utah to prioritize variants in familial POI and cancer. We will also examine de novo mutation rate as an additional mechanism for cancer risk in these women. Variants will be replicated in data from large biobanks and functionally assessed in our D. melanogaster functional model and a new DNA damage cell-based assay. Specific Aim 3 will combine genetic and demographic data from the UPDB with clinical data from the electronic medical record (EMR) in women with POI to create a cancer prediction and assessment tool. The portability of the tool will be tested in an outside health system. The work addresses fertility as a marker of overall health by examining the cause of increased cancer in diseases associated with decreased ovarian reserve, particularly in women with POI. Early identification of risk associated with a POI diagnosis will inform our recommendations for careful medical follow up and hormone replacement therapy in at-risk women.

Narrative The proposal will determine whether the etiology of increased cancer risk in women with primary ovarian insufficiency (POI) and their family members has a shared genetic cause with POI or results from an increased mutation rate. These studies will also develop an artificial intelligence tool to predict cancer and other disease risk in women with POI.