Elucidating pathways underlying the association of contraception use with ovarian cancers through metabolic profiling

PROJECT SUMMARY/ABSTRACT The overarching goal of this project is to comprehensively quantify changes in metabolites and pathways (collectively, the metabolomic profile) associated with oral contraception (OC) use to elucidate mechanisms involved in ovarian and breast carcinogenesis. Ovarian cancer (OvCa) is the 5th most common cause of cancer death among females, but risk is 15-30% lower among women who have ever used OCs. Conversely, epidemiologic studies also show modest but significant increased risk of breast cancer (BrCa), the most common cancer of US women, with OC use. One approach for disentangling the effects of OCs on cancer risk and elucidating etiology is the integration of metabolomics into epidemiologic research. Recent studies support circulating plasma metabolites and metabolite groups are associated with OvCa and BrCa, and that OCs can change metabolomic profiles. However, key barriers to determining the mechanisms of OC use that contribute to cancer risk include: 1) limited details of OC use in large cohorts (e.g. formulation, duration, age at first use), 2) inadequate consideration of individual variability in physiologic response to OC use (e.g. metabolizing enzyme activity, endometriosis (OvCa risk factor), family history of OvCa/BrCa), and 3) lack of biospecimens representing the local environment relative to the cancer site of origin (e.g. peritoneal cavity for OvCa). Dr. Mongiovi will address these limitations in an assessment of metabolites associated with OC use using a machine learning and systems biology approach. Leveraging data from the Nurses’ Health Studies (NHS, NHSII) and the Women’s Health Study: From Adolescence to Adulthood (A2A), Aim 1 (K99) will identify circulating metabolomic profiles of current OC use among premenopausal women and prior OC use among postmenopausal women and evaluate differences by genetic variants in hormone biosynthesis and metabolism pathways, endometriosis status, and family history. Metabolite profile scores of current and prior OC use will be developed and the association of each metabolite score with risk of OvCa and BrCa will be determined in nested case-control studies within NHS/NHSII. Aim 2 (R00) will characterize local metabolomic profiles relative to the development of BrCa in normal breast tissue from then Komen Tissue Bank, OvCa using previously collected peritoneal fluid from A2A participants, and novel assessment of vaginal fluid among women recruited from local clinics. The proposed research will elucidate how OCs alter OvCa and BrCa risk by comprehensively assessing systemic and local metabolomic profiles. By disentangling the processes through which OC leads to reduced OvCa and increased BrCa risk through metabolomic profiling, we can improve risk prediction and identify targets for prevention and interception. During the K99 phase, Dr. Mongiovi will follow a well-rounded training plan in support of these aims developing proficiency in analysis and interpretation of omics data and cultivating expertise in ovarian and breast tumorigenesis. This K99/R00 award will support her in obtaining the knowledge and experience to effectively pursue a career as an independent, interdisciplinary researcher in female cancers.