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.

中文翻译：

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与卵巢癌风险相关的循环血浆代谢产物的前瞻性分析。

卵巢癌几乎没有已知的危险因素，这妨碍了对高危妇女的识别。我们评估了诊断前血浆代谢物（N = 420）与上皮性卵巢癌（包括交界性和浸润性肿瘤）的风险之间的关系。纳入了252例病例和252例来自护士健康研究的匹配对照。使用基于排列的Westfall和Young方法来检验多重相关假设，使用多变量logistic回归来估计比值（OR）和95％置信区间（CI），比较代谢物水平的第90-10％。还评估了加权基因共表达网络分析（WGCNA）模块（n = 10个代谢物模块）和代谢物组富集分析（MSEA； n = 23个代谢物类别）。伪尿苷水平从第10个百分点增加到第90个百分点与总体卵巢癌风险增加2.5倍相关（OR = 2.56，95％CI = 1.48-4.45； p = 0.001 / adjusted-p = 0.15）；对于浆液性/分化差的肿瘤（n = 176例；可比的OR = 2.38，95％CI = 1.33-4.32，p = 0.004 /校正后的-p = 0.55），观察到了相似的风险估计。对于非浆液性肿瘤（n = 34例）中，假尿苷和C36：2磷脂酰胆碱（PC）缩醛磷脂具有最强的统计学联系（可比OR = 9.84，95％CI = 2.89-37.82; p <0.001 / adjusted-p = 0.07; OR = 0.11，95％ CI = 0.03-0.35； p <0.001 / adjusted-p = 0.06）。五个WGCNA模块和9个类别与FDR≤0.20时的总体风险相关。三酰基甘油（TAGs）通过肿瘤侵袭性表现出异质性（仅案例异质性- p <0.0001）。TAG与高危及浆液性肿瘤的相关性因酰基碳含量和饱和度而异。总而言之，这项研究表明假尿苷可能是卵巢癌的一种新的危险因素，TAGs也可能很重要，尤其是对于快速致命的肿瘤，其关联因结构特征而异。