The aims of the study are to gain a better understanding of the etiologic role of inflammation markers, including cytokines, in endometrial cancer and ovarian carcinoma development. Evaluating associations between elevated cytokine levels and cancer risk might clarify the role of inflammation in carcinogenesis and provide a new means of identifying women at risk of developing either cancer type. Primary aims: 1. To evaluate the association of pre-diagnostic circulating levels of CRP with incident endometrial cancer and ovarian carcinoma. To our knowledge, one prospective study has evaluated CRP and endometrial cancer risk showing a positive association. Further, two prospective studies have examined relationships between CRP and ovarian cancer risk, both showing similar relationships between higher levels of CRP and elevated risk, but neither having the statistical power to make this important finding definitive. 2. To analyze our data together with existing data from a study of inflammation markers and incident ovarian cancer completed by Dr. Alan Arslan (NYU) and colleagues. 3. To evaluate the association of pre-diagnostic cytokines associated with obesity and/or diabetes (IL-1alpha, IL-6, IL-8, TNF-alpha, leptin, MCP-1, MIP-1alpha) and incident endometrial cancer. We hypothesize that inflammation markers associated with obesity or type II diabetes, known hyper-inflammatory states, are associated with increased risk of endometrial cancer and ovarian carcinoma. 4. To evaluate the association of pre-diagnostic cytokines involved in ovarian function (IL-1alpha, IL-6, IL-8, TNF-alpha, IFN-gamma, M-CSF, G-CSF, MG-CSF) and incident ovarian carcinoma. We hypothesize that inflammation markers involved in ovarian function and associated with epithelial inflammation are associated with increased risk of endometrial cancer and ovarian carcinoma. Secondary aims: 1. To explore the association of over 50 additional pre-diagnostic circulating inflammation markers and known risk factors with incident endometrial cancer and ovarian carcinoma. We plan to measure serum levels of the remaining approximately 50 markers related to inflammation (see Table 1) in two nested case-control study (300 invasive endometrial cancers and 150 ovarian carcinomas and 300 shared controls) using a bead-based multiplex assay. We hypothesize that higher levels of pro-inflammatory markers and lower levels of anti-inflammatory markers are associated with increased risk of endometrial cancer and ovarian carcinoma. 2. To evaluate the relationship between inflammation marker levels and time to cancer diagnosis. 3. Our project will contribute data from a subset of inflammation markers (IL-6, CRP, TNF-alpha, TNF-alpha receptors 1 and 2, MCP-1, and leptin) to the EEMS proposal "Inflammation, Vitamin D Exposure, and Endometrial Cancer Risk: A Consortium Study" (PI: A.R. Kallianpur) and pursue additional pooled analyses of the endometrial cancer data with cohorts in the Epidemiology of Endometrial Cancer Consortium (E2C2). 4. To study associations of cytokines or other inflammation markers with risk factors among controls, including age, BMI, diabetes, and season of blood draw, as well as other measured analytes, including estrogens, which are reported to be immunomodulators. To combine our data with data from two existing case-control studies of CRP and incident ovarian carcinoma through the Ovarian Cancer Cohort Consortium (OC3). Our project will contribute data from a subset of inflammation markers (IL-6, CRP, TNF-alpha, TNF-alpha receptors 1 and 2, MCP-1, and leptin) to the EEMS proposal "Inflammation, Vitamin D Exposure, and Endometrial Cancer Risk: A Consortium Study" (PI: A.R. Kallianpur) and pursue additional pooled analyses of the endometrial cancer data with cohorts in the Epidemiology of Endometrial Cancer Consortium (E2C2). a. We will conduct a meta-analysis including CRP, IL-2, IL-4, IL-6, IL-10, IL-12p40, TNF-alpha, IL-1RA, sIL-IRII, sIL-2RA, sIL-4R and sIL-6R measured in 230 ovarian cancer cases and controls from three studies (NYUHS, ORDET, NSHDS) on the same Luminex platform we propose to use for PLCO. The combined analysis of the overlapping markers between Dr. Arslan's study and PLCO and the additional discovery set of approximately 50 markers measured PLCO alone will constitute stage I of a multi-cohort approach to study inflammation and ovarian cancer risk. The 10-20 most promising markers will be validated in the Ovarian Cancer Cohort Consortium (OC3), a new consortium that has formed under the umbrella of the Cohort Consortium. In OC3, at least 1000 ovarian cancers cases with prediagnostic blood samples will be available for validation. (Figure 1)

Amanda Black (CCR&DCEG,NCI,NIH)
Louise Brinton (HREB,DCEG,NCI,NIH)
Anil Chaturvedi (IIB,DCEG,NCI,NIH)
Patricia Hartge (EBP,DCEG,NCI,NIH)
Ruth Pfeiffer (BB,DCEG,NCI,NIH)
Ligia Pinto (SAIC,Frederick,NCI,NIH)
Mark Sherman (HREB,DCEG,NCI,NIH)
Britton Trabert (HREB,DCEG,NCI,NIH)
Nicolas Wentzensen (HREB,DCEG,NCI,NIH)