Determinants of breast tissue composition in young women

描述（由申请人提供）：这里提出的研究的长期目标是产生可以应用于年轻女性预防乳腺癌的新知识。“乳腺组织年龄”的Pike理论模型和经验流行病学证据表明，乳房在早期特别容易受到致癌物的影响，并建议如果在生命早期开始预防乳腺癌的策略将是最有效的。先前的研究表明，乳房x线摄影密度（PMD）百分比的变化与中年和老年女性患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。受此启发，我们使用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。乳房磁共振成像已被用于描述所有年轻女性和100名母亲的乳房组织特征。15-18岁的年轻女性乳房含水量的平均水平和变化最大，这一年龄段对致癌物的易感性也最大。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，这表明生长发育的一般指标与乳房组织组成有关。与先前描述的遗传影响一致，年轻女性的乳房含水量也与母亲的MR和PMD的乳房含水量有关。我们还发现，所有受试者血液中生长激素和性激素结合球蛋白的水平都与乳房含水量有关。因此，我们有证据表明，荷尔蒙和遗传因素都会影响年轻女性的乳腺组织组成。我们在此建议招募更多的年轻女性（年龄在15-18岁之间），以提供足够大的样本来检查基因组中常见的遗传变异和乳房组织的表型特征。这个样本也将使我们能够重新检查激素和生长因子与这个年龄组乳腺组织组成的关系。迄今完成的工作表明，征聘实现这些目标所需的年轻妇女人数是可行的。我们将在收集了DNA和乳房x线照片的绝经前年轻女性中重复基因组全关联研究的结果。据我们所知，这是对年轻女性乳房组织的第一次广泛研究，也是迄今为止唯一一项表明内源性性激素与该年龄组乳房组织组成之间存在关联的研究。

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.