Determinants of breast tissue composition in young women

描述（由申请人提供）： 这项研究的长期目标是产生新的知识，可以应用于年轻女性预防乳腺癌。“乳房组织年龄”的理论派克模型和经验流行病学证据表明，乳房在幼年时特别容易受到致癌物的影响，并表明预防乳腺癌的策略如果在生命早期开始，将是最有效的。以前的研究表明，乳腺摄影密度百分比（PMD）的变化与中年和老年妇女乳腺癌风险的巨大差异有关，具有高度遗传性，并且与磁共振（MR）评估的乳房含水量密切相关，我们已经使用MR检查了与年轻女性乳房组织变化相关的因素。迄今为止，我们已经检查了400名年轻女性（15-30岁）及其母亲。乳腺MR已被用于描述所有年轻女性和100名母亲的随机样本的乳腺组织。乳房含水量的平均水平和变化在15-18岁的年轻妇女中最大，这一年龄段对致癌物的敏感性也最大。我们发现，年轻女性的乳房含水量与她们的体重和身高相关，这表明生长和发育的一般措施与乳房组织成分有关。与先前描述的遗传影响一致，年轻女性的乳房含水量也与其母亲的MR和PMD的乳房含水量相关。我们还发现，所有受试者的生长激素和性激素结合球蛋白的血液水平与乳房含水量有关。因此，我们有证据表明激素和遗传因素都会影响年轻女性的乳房组织成分。我们建议招募更多的年轻女性（15-18岁）加入到已经检查的人群中，以提供足够大的样本来检查基因组中的常见遗传变异和乳腺组织的表型特征。该样本还将使我们能够重新检查激素和生长因子与该年龄组乳腺组织组成的相关性。迄今为止完成的工作表明，招聘实现这些目标所需数量的年轻妇女是可行的。我们将在绝经前的年轻妇女中复制全基因组关联研究的结果，从这些妇女中收集DNA和乳房X线照片。 据我们所知，这是第一次对年轻女性乳房组织进行广泛的研究，也是迄今为止唯一一项显示内源性性激素与该年龄组乳房组织成分相关的研究。 公共卫生相关性： 我们建议招募年轻女性和她们的母亲，以补充已经检查过的样本，提供足够大的样本来研究与乳腺组织组成变化相关的基因，并提供数据来证实以前有关激素和乳腺组织组成的研究结果。这项研究将探讨基因型和乳腺组织表型特征之间的关系。迄今为止完成的工作表明，招聘实现这些目标所需数量的年轻妇女是可行的。据我们所知，这是第一次对年轻女性的乳腺组织进行广泛的研究，此时对致癌事件的易感性最大，乳腺组织成分的变化也最大。此外，怀孕、更年期和其他与衰老有关的因素尚未影响乳房组织的组成。由于这些原因，在早期可能更容易发现遗传效应，以及早期生活特有的环境暴露的影响。

DESCRIPTION (provided by applicant): The long-term goal of the research proposed here is to generate new knowledge that can be applied to young women to prevent breast cancer. The theoretical Pike model of "breast tissue age", and empirical epidemiological evidence, indicate that the breast is especially susceptible to the effects of carcinogens at early ages, and suggest that strategies of breast cancer prevention will be most effective if started early in life. Motivated by previous work that has shown variations in percent mammographic density (PMD) to be associated with large differences in risk of breast cancer in women of middle age and older, to be highly heritable, and strongly correlated with the water content of the breast as assessed by magnetic resonance (MR), we have examined factors associated with variations in breast tissue in young women using MR. To date we have examined 400 young women (aged 15-30 years), and their mothers. Breast MR has been used to characterize breast tissue in all young women and a random sample of 100 mothers. Mean levels and variation in breast water content were greatest in young women aged 15-18 years, when susceptibility to carcinogens is also greatest. We have found that the breast water content in young women is correlated with their weight and height, suggesting that general measures of growth and development are associated with breast tissue composition. Consistent with a previously described genetic influence, breast water content in young women was also associated with both the breast water content by MR and PMD of their mothers. We also found that blood levels of growth hormone and sex hormone binding globulin in all subjects were associated with breast water content. We thus have evidence that both hormonal and genetic factors influence breast tissue composition in young women. We propose here to recruit additional young women (aged 15-18 years) to add to those already examined, to provide a sample large enough to examine common genetic variation across the genome and the phenotypic features of breast tissue. This sample will also allow us to re-examine the associations of hormones and growth factors with breast tissue composition in this age group. The work completed to date has shown the feasibility of recruiting the number of young women required to achieve these aims. We will replicate results from the genome wide association study in young women in premenopausal women from whom DNA and collected and mammograms have been collected. To the best of our knowledge this is the first extensive study of breast tissue in young women, and the only study to date to show an association of endogenous sex hormones with breast tissue composition in this age group. PUBLIC HEALTH RELEVANCE: We propose to recruit young women, and their mothers, to add to those already examined, to provide a sample large enough for studies of genes associated with variations in breast tissue composition, and to provide data to confirm findings from previous work concerned with hormones and breast tissue composition. The proposed study will examine the relationship between genotype and the phenotypic features of breast tissue. The work completed to date has shown the feasibility of recruiting the number of young women required to achieve these aims. To the best of our knowledge this is the first extensive study of breast tissue in young women, when susceptibility to carcinogenic events is greatest, and variation in breast tissue composition is also greatest. Further, pregnancy, menopause, and other factors associated with ageing have not yet influenced breast tissue composition. For these reasons it may be easier at early ages to detect genetic effects, as well as the effects of environmental exposures unique to early life.