Early Determinants of Mammographic Density

描述（由申请人提供）：大量研究表明，胎儿生长标志物与成人健康的重要领域之间存在关联。特别是，最近的几项研究表明，高出生体重可能与以后患乳腺癌的风险增加有关。现有的关于出生体重和乳腺癌风险的文献，虽然有趣，但由于无法解决以下问题而福尔斯不足：（1）家庭因素的潜在混杂（例如，社会经济地位）;（2）其他胎儿生长指标的重要性及其可能的相互作用;（3）母体特征和暴露的独立影响;（4）潜在的生物学机制;（5）出生后生长的贡献;（6）成人风险因素的介导。我们将通过使用一种新的研究设计来解决这些局限性，该研究设计检查了早期生命因素与乳腺摄影密度的关联，乳腺摄影密度是未来乳腺癌风险的强有力预测因素。具体而言，我们将招募325对女性的同胞样本（n=650）和350名高出生体重（>= 4000 g）女性的独生子女样本，共计1000名受试者。所有女性均为1959年至1967年期间在国家围产期合作项目（NCPP）和儿童健康与发育研究（CHDS）的两个新英格兰地点（波士顿和普罗维登斯）登记的孕妇的后代。兄弟姐妹设计将允许我们控制家庭效应，例如可能影响出生体重和成人风险因素模式的社会经济地位。暴露信息将来源于前瞻性收集的母亲、婴儿和儿童生长的产前和产后数据。在妊娠晚期期间收集的母体血清将用于测量雌激素（E1、E2、E3）和睾酮。沿着乳房X光检查，我们还将通过访谈和实验室测定（包括IGF-I、IGFBP-3的测量）收集成人风险因素数据。我们假设高出生体重、高胎盘重量、高胎盘/出生体重比、高母体妊娠体重增加和高母体雌激素水平会增加女儿的乳腺X线摄影密度，而母体先兆子痫和较高水平的母体睾酮会降低女儿的乳腺X线摄影密度。我们将进一步研究这些关联是否由儿童生长模式和成人风险因素介导。这项研究将通过直接解决现有文献中的许多局限性来推进关于乳腺癌风险早期决定因素的文献，从而更彻底地检查可能形成早期乳腺癌易感性的因素。

DESCRIPTION (provided by applicant): Numerous studies have shown associations between markers of fetal growth and important domains of adult health. In particular, several recent studies suggest that high birth weight may be associated with an increased risk of breast cancer later in life. The existing literature on birth weight and breast cancer risk, while intriguing, falls short by its inability to address the following: (1) potential confounding by family factors (e.g., socioeconomic status); (2) the importance of and possible interaction with other measures of fetal growth; (3) the independent effect of maternal characteristics and exposures; (4) potential biological mechanisms; (5) the contribution of postnatal growth; and (6) mediation by adult risk factors. We will address these limitations by use of a novel study design examining the association of early life factors with mammographic density, a strong predictor of future breast cancer risk. Specifically, we will recruit a sibling sample of 325 female pairs (n=650) and a single child sample of 350 high birth-weight (>=4000g) females for a total of 1000 subjects. All females are offspring of pregnant women enrolled during 1959 to 1967 in two New England sites (Boston and Providence) of the National Collaborative Perinatal Project (NCPP) and in the Childhood Health and Development Study (CHDS). The sibling design will allow us to control for family effects such as socioeconomic status that may influence both birth-weight and adult risk factor patterns. Exposure information will be derived from prospectively collected pro and postnatal data on mothers, infants, and childhood growth. Maternal sera collected during the third trimester will be used to measure estrogen (El, E2, E3), and testosterone. Along with the mammogram, we will also collect adult risk factor data through interview and laboratory assays (including measures of IGF-I, IGFBP-3). We hypothesize that high birth weight, high placental weight, high placental/birth weight ratio, high maternal pregnancy weight gain, and high maternal estrogen levels will increase mammographic density in the daughters, and that maternal preeclampsia and higher levels of maternal testosterone will decrease mammographic density in the daughters. We will further examine whether any of these associations are mediated by childhood growth patterns and adult risk factors. This study will advance the literature on early determinants of breast cancer risk by directly addressing many of the limitations in the existing literature, allowing a more thorough inspection into what may shape early breast cancer susceptibility.