A prospective analysis of circulating plasma metabolites associated with ovarian cancer risk.

Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of pre-diagnostic plasma metabolites (N=420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10 metabolite modules) and metabolite set enrichment analysis (MSEA; n=23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15); a similar risk estimate was observed for serous/poorly-differentiated tumors (n=176 cases; comparable OR=2.38, 95%CI=1.33-4.32, p=0.004/adjusted-p=0.55. For non-serous tumors (n=34 cases), pseudouridine and C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical associations (comparable OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07; and OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR≤0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features.