PO.PS01.01 · 人群科学
护士健康研究II中绝经前女性口服避孕药使用与乳腺癌和卵巢癌相关的血浆代谢组学特征
Plasma metabolomic profiles of oral contraception use associated with breast and ovarian cancers among premenopausal women in Nurse's Health Study II
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摘要 Abstract
中文摘要
背景:虽然超过80%的性活跃绝经前女性使用口服避孕药(OC),但将OC与激素敏感性癌症联系起来的生物学机制尚不清楚。OC使用可降低卵巢癌风险,而当前使用会适度增加乳腺癌风险,提示存在复杂的潜在通路。我们试图识别绝经前女性中与OC使用相关的血浆代谢物及其与卵巢癌和乳腺癌的关系。方法:分析纳入了护士健康研究II中2,072名有自我报告OC史的绝经前女性。OC使用定义为既往使用≥1年,排除当前使用者。所有代谢物值均转换为probit评分以实现正态性。通过多变量线性回归评估既往使用≥1年与从未使用以及每5年使用与个体代谢物的关联,并根据解释90%方差的主成分数量考虑有效检验数(NEF)。通过代谢物集富集分析(MSEA)使用错误发现率(FDR)进行多重检验以识别代谢物组。OC使用模型对采血变量(年龄、时间、季节、空腹状态)、BMI、吸烟、饮食(替代健康饮食指数评分)、饮酒和采血时的体力活动进行了校正。代谢物组(FDR<0.20)和代谢物(NEF<0.20)的关联被视为与OC使用名义相关。使用条件逻辑回归评估与采血后至少≥3年诊断的新发乳腺癌(n=663)和卵巢癌(n=34)的关联,使用按采血变量1:1匹配的对照,对年龄、OC持续时间、产次以及乳腺癌或卵巢癌家族史进行校正,并使用MSEA。结果:在2,703名女性中,1,681名(81.1%)报告既往使用OC≥1年,平均持续时间为4.0±3.9年。每额外使用5年OC与更高的C40:6磷脂酰乙醇胺(PE)水平相关(beta =0.09;95% CI:0.04, 0.14),磷脂酰胆碱和PE均与OC使用和持续时间呈负相关,但与乳腺癌和卵巢癌风险呈正相关。OC持续时间增加与更低的色氨酸(beta =-0.11;95% CI:-0.16, -0.05)和更高的1,7-甲基尿酸(beta =-0.11;95% CI:-0.16, -0.05)相关,这两者在乳腺癌病例中均较低,而在卵巢癌病例中较高,但整个有机杂环化合物组与OC使用无显著相关。结论:我们的结果表明,系统性代谢的长期改变可能部分解释了OC使用与乳腺癌和卵巢癌的关联,尤其是在参与脂质代谢的代谢物中。分析仍在进行中,将包括对OC使用的时机和剂型以及癌症亚型的更深入研究。
查看英文原文 English abstract
BACKGROUND: While over 80% of sexually active premenopausal women use oral contraception (OC), the biological mechanisms linking OC to hormone-sensitive cancers are not well understood. OC use lowers ovarian cancer risk while current use modestly increases breast cancer risk, suggesting complex underlying pathways. We sought to identify plasma metabolites associated with OC use in premenopausal women and relationships with ovarian and breast cancer. METHODS: Analysis included 2,072 premenopausal women in Nurses' Health Study II with self-reported OC history. OC use was defined as ≥1 years of previous use, excluding current users. All metabolite values were transformed to probit scores to achieve normality. Associations of prior use ≥1 years versus never and per 5 years use with individual metabolites were evaluated through multivariable linear regression, accounting for the number of effective tests (NEF) based on the number of principal components explaining 90% of the variance. Metabolite groups were identified through metabolite set enrichment analysis (MSEA) using false discovery rate (FDR) for multiple testing. OC use models were adjusted for blood draw variables (age, time, season, fasting status), BMI smoking, diet (Alternative Healthy Eating Index score), alcohol consumption, and physical activity at the time of blood draw. Associations of metabolite groups (FDR<0.20) and metabolites (NEF<0.20) were considered nominally associated with OC use. Associations with incident breast (n=663) and ovarian cancers (n=34) diagnosed at least ≥3 years after blood draw were assessed using conditional logistic regression, using controls matched 1:1 on blood draw variables, adjusting for age, OC duration, parity, and family history of breast or ovarian cancer and using MSEA. RESULTS: Of 2,703 women, 1,681 (81.1%) reported having previously used OC for ≥1 year, with a mean duration of 4.0±3.9 years. Each additional 5 years of OC use was associated with higher C40:6 phosphatidylethanolamines (PE) levels ( beta =0.09; 95% CI: 0.04, 0.14), and both phosphatidylcholines and PEs were negatively associated with OC use and duration but positively for breast and ovarian cancer risk. Increasing OC duration was associated with lower tryptophan ( beta =-0.11; 95% CI: -0.16, -0.05) and higher 1,7-methyluric acid ( beta =-0.11; 95% CI: -0.16, -0.05), which were both lower among breast cancer cases and higher among ovarian cancer cases, but the overall organoheterocyclic compound group was not significantly associated with OC use. CONCLUSION: Our results suggest long-lasting alterations of systemic metabolism may in part explain associations of OC use with breast and ovarian cancers, particularly among metabolites that contribute to lipid metabolism. Analyses are ongoing and will include a deeper investigation into timing and formulation of OC use as well as cancer subtypes.
利益披露 Disclosure
J. M. Mongiovi, None.