The Two Sister Study

两姐妹研究

• 批准号: 8553788
• 负责人: Clarice Weinberg
• 金额: $ 30.77万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553788
• 关键词: Affect; Aftercare; Age; Authorization documentation; Blood; Breast Cancer Treatment; Cancer Survivor; Candidate Disease Gene; Clinical; Clinical Data; Complex; Computer Assisted; Contract Services; Contracts; DNA; Data; Detection; Development; Diagnosis; Disease; Enrollment; Environment; Environmental Risk Factor; Exposure to; Family; Fertility Agents; First Pregnancy Trimester; Funding; Funding Agency; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Health; Hormonal; Hormones; Inherited; Joints; Journal of the National Cancer Institute; Literature; Logistic Regressions; Mammary Gland Parenchyma; Mediating; Menopause; Methylation; Modeling; Newly Diagnosed; Nuclear Family; Occupational Exposure; Ovulation; Paired Comparison; Paper; Parents; Postdoctoral Fellow; Pregnancy; Prospective Studies; Publishing; Questionnaires; Recording of previous events; Recruitment Activity; Recurrence; Reproductive History; Research; Research Infrastructure; Risk; Role; Saliva; Secure; Sister; Site; Statistical Methods; Symptoms; Telephone Interviews; Woman; Work; base; cancer risk; cohort; cost; cost effective; design; exome; experience; family structure; follow-up; genetic variant; genome wide association study; imprint; malignant breast neoplasm; novel; outcome forecast

This Komen-funded study has recruited women with young-onset breast cancer and, when available, their parents. We will combine their data with the DNA and environmental data now being collected from their unaffected sisters (who previously joined the Sister Study) and saliva-based DNA collected from their parents. We will use a nuclear-family-based approach to study genetic and environmental factors involved in young-onset breast cancer. The study gains enormous operational efficiency advantages, by taking advantage of the infrastructure that is already in place and functioning smoothly for the Sister Study (Dale Sandler, PI). We are almost done with collecting clinical data and validating the diagnoses for all these young-onset cases. Follow-up of these cases (through the Sister Study) will also allow us to identify environmental, clinical, and genetic factors that influence health after treatment. Case-parent analyses of gene variants are protected against bias due to confounding by genetic heritage, and also permit detection of both maternally-mediated genetic effects and parent-of-origin (imprinting) effects. In the proposed study, the participating affected sisters are each completing a computer-assisted telephone interview like the one their sister completed for the Sister Study, providing information about personal exposures, reproductive history, and past occupational exposures. Environmental effects will be identifiable through a paired comparison of affected and unaffected sisters. Gene-by-exposure interactions will be assessed with novel statistical methods. In summary, the proposed study leverages off the ongoing Sister Study to build a cost-effective, powerful, and statistically independent study of young-onset breast cancer. Findings related to combined effects of genetic variants and environmental factors can be replicated later in the Sister Study. We have completed study enrollment. With augmentation by including some newly diagnosed young-onset cases from the Sister Study we have enrolled nearly 1500 cases providing both questionnaire data and DNA. We have also enrolled 1403 of their parents, who provided DNA. This work was accomplished with assistance from the EB support services contract. We recently secured permission from the funding agency (Susan G. Komen for the Cure) for a no-cost extension and for redirecting the money originally intended for a candidate gene approach to instead carry out a GWAS, using the Illumina OmniExpress plus Exome chip. Carried out through a contract with the Center for Inherited Disease Research, this genotyping project should deliver more than a million SNPs on these families. The final DNA extractions are now being done and the genotyping will be accomplished in the next few months. We hope to use these data to find gene-by-environment causal factors for young onset breast cancer. By combining the Two Sister cases with those arising in the Sister Study we will also be able to study complexes of factors that are related to healthy recurrence-free survival following treatment. Together with a postdoc, Chunyuan Fei, we published two papers this year based on the Two Sister Study. In the first, we looked at history of exposure to ovulation-stimulating fertility drugs. These exposures have hormonal effects that have raised concerns about breast cancer, but literature has been mixed. We recognized that the exposures are different if a pregnancy occurs, because the levels of hormones remain elevated for the first trimester of pregnancy, potentially influencing the remodeling of breast tissue. Based on a conditional logistic regression model exposed women had reduced risk compared to the unexposed, but that apparent protection was lost if the treatment led to a pregnancy. We have another paper in press related to the apparent protection enjoyed by women who have a history of menopause-associated symptoms. We have several papers related to the Sister Study. One, which has been provisionally accepted at the Journal of the National Cancer Institute evaluated methylation at about 27,000 CpG sites in the genome using blood that had been collected at baseline and related those results to the later development of breast cancer. Methylation status was predictive of risk of cancer.

这项由Komen资助的研究招募了患有年轻乳腺癌的妇女，并在可能的情况下是父母。我们将将他们的数据与目前从未受影响的姐妹（以前加入姐妹研究）和从父母那里收集的基于唾液的DNA中收集的DNA和环境数据相结合。 我们将使用一种基于核家庭的方法来研究涉及年轻乳腺癌的遗传和环境因素。 这项研究通过利用已经到位的基础设施并为姊妹研究平稳运行（Dale Sandler，PI），从而获得了巨大的运营效率优势。 我们几乎完成了收集临床数据并验证所有这些年轻人病例的诊断。 这些病例的随访（通过姐妹研究）还将使我们能够识别影响治疗后影响健康的环境，临床和遗传因素。 由于遗传遗产的混淆，对基因变异的病例分析受到保护，还可以检测到母体介导的遗传效应和父母 - 源源物（印迹）效应。 在拟议的研究中，参与的受影响的姐妹分别完成了计算机辅助的电话采访，就像他们的姐姐完成姐妹学习的那样，提供了有关个人暴露，生殖历史和过去职业接触的信息。 通过对受影响和未受影响的姐妹的配对比较，可以识别环境影响。 逐个暴露基因的相互作用将通过新型统计方法进行评估。 总而言之，拟议的研究利用正在进行的姐妹研究来建立对年轻乳腺癌的成本效益，强大且统计上独立的研究。 在姊妹研究的稍后，可以复制与遗传变异和环境因素的综合作用相关的发现。 我们已经完成了学习入学率。 通过包括一些新诊断的年轻案例，我们从姐妹研究中包括了近1500例提供问卷数据和DNA的病例。 我们还招募了1403位提供DNA的父母。这项工作是在EB支持服务合同的协助下完成的。最近，我们获得了资助机构（Susan G. Komen进行治疗）的许可，以进行无成本延长，并将最初用于候选基因方法最初的资金重定向，而是使用Illumina Omniexpress Plus Exome plus Exome芯片。通过与遗传性疾病研究中心的合同实现的基因分型项目应为这些家庭提供超过一百万个SNP。现在正在完成最终的DNA提取，并且基因分型将在未来几个月内完成。 我们希望使用这些数据为年轻发作乳腺癌找到基因因果因素。 通过将两个姐妹病例与姊妹研究中产生的病例相结合，我们还将能够研究与治疗后与健康无复发生存有关的因素的复合物。 我们与博士后Chunyuan FEI一起，根据两项姐妹研究，今年发表了两篇论文。 首先，我们研究了暴露于排卵刺激的生育药物的史。 这些暴露具有激素作用，引起了人们对乳腺癌的关注，但文献却混杂在一起。 我们认识到，如果发生怀孕，暴露率有所不同，因为妊娠的头三个月的激素水平仍然升高，可能会影响乳腺组织的重塑。 基于条件逻辑回归模型，暴露的妇女与未暴露的妇女相比降低了风险，但是如果治疗导致妊娠，则显然保护了这种保护。 我们还有另一篇论文与具有更年期相关症状史的女性所享有的明显保护。 我们有几篇与姐妹研究有关的论文。其中一项是在国家癌症研究所杂志上被临时接受的，该杂志使用基线收集的血液在基因组中的约27,000名CPG部位评估了甲基化，并将这些结果与后来的乳腺癌发展相关。 甲基化状态是癌症风险的预测。