The Two Sister Study

两姐妹研究

• 批准号: 8929794
• 负责人: Clarice Weinberg
• 金额: $ 129.32万
• 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/8929794
• 关键词: Affect; Aftercare; Age; Authorization documentation; Award; Biological Assay; Birth; Breast Cancer Risk Factor; Breast Cancer Treatment; Cancer Survivor; Candidate Disease Gene; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Data; Cohort Effect; Cohort Studies; Complex; Complication; Computer Assisted; Contract Services; Contracts; DNA; Data; Databases; Detection; Diagnosis; Disease; Eating Disorders; Enrollment; Environment; Environmental Risk Factor; Estrogens; Event; Exposure to; Family; Funding; Funding Agency; Genes; Genetic; Genotype; Goals; Grant; Habits; Health; Hormone replacement therapy; Inherited; Joints; Logistic Models; Mediating; Menopause; Menstrual cycle; Methylation; Migraine; Modeling; Newly Diagnosed; Noninfiltrating Intraductal Carcinoma; Nuclear Family; Occupational Exposure; Paired Comparison; Paper; Parents; Patient Self-Report; Pattern; Postdoctoral Fellow; Probability; Progesterone; Prospective Studies; Publications; Publishing; Questionnaires; Recording of previous events; Recruitment Activity; Recurrence; Reporting; Reproductive History; Research; Research Infrastructure; Research Personnel; Risk; Risk Factors; Role; Saliva; Secure; Sister; Specimen; Statistical Methods; Surveys; Survivors; Telephone Interviews; Time; United States National Institutes of Health; Vitamin D; Woman; Women' s Health; Work; base; cancer risk; clinical practice; cohort; cost; cost effective; design; dietary supplements; exome; experience; family structure; follow-up; genetic analysis; genetic variant; genome wide association study; imprint; interest; malignant breast neoplasm; novel; outcome forecast; reproductive

This Komen-funded study recruited women with young-onset breast cancer, an unaffected sister already being studied as part of the Sister Study cohort, 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 are using a nuclear-family-based approach to study genetic and environmental factors involved in young-onset breast cancer. The study gained enormous operational efficiency advantages, by taking advantage of the infrastructure that was 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 (after merging with new cases in 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 Two Sister 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 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 genome-wide association study (GWAS), using the Illumina OmniExpress plus Exome chip. Carried out through a contract with the Center for Inherited Disease Research, this genotyping project has (augmented by imputations) generated more than 20 million SNPs on these families. We are also participating in the GAME-ON consortium, and this effort has provided additional genotype data based on the newly developed oncochip, again through CIDR. We are using these data to find gene-by-environment causal factors for young onset breast cancer. By combining the Two Sister cases with those incident cases 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. There is interest in a possible relation between history of migraine headache and risk of breast cancer, and we carried out analyses related to that question using data from the Two Sister Study. We distinguished between migraines that tended to occur at a particular time of the menstrual cycle and those that did not follow a menstrual pattern. Overall there was no relationship between migraine and risk of young-onset breast cancer. That paper is now undergoing review. In work with my new post-doc, Katie O'Brien, we considered history of exposure to hormone replacement therapy (HRT) and risk of young onset breast cancer, using data from the Two Sister Study. A complication to overcome in carrying out that analysis was a birth cohort effect related to the publication in 2002 of findings from the Women's Health Initiative trial where the combination estrogen/progesterone hormone replacement therapy was found to increase risk of breast cancer and other conditions. As that report had an effect on clinical practice, women who and gone through menopause prior to 2002 were more likely to have used HRT than were their younger sisters who went through menopause after those findings had been published. Because the control sisters tended to be older than their case sister in the Two Sister Study, this birth cohort effect implied that controls were more likely to have been prescribed hormone replacement therapy. To adjust for this differential opportunity for exposure we carried out a propensity score analysis where we used data from the Sister Study to model the likelihood of exposure and applied those propensity probabilities to the logistic model using data from the Two Sister Study. The resulting paper is now undergoing review. A second paper undergoing review compares the risk factor profiles for ductal carcinoma in situ and invasive breast cancer for women with diagnosis under age 50, again using data from the Two Sister Study. This work was joint with our undergraduate summer intern from last summer, Jenny Sun. In work this past summer with an intern, Denis Whelan, we considered self-reported history of a young-onset eating disorder in relation to risk factors for breast cancer and described associations with later body habits and reproductive events. Analyses of the genetic data are ongoing. We applied for and were awarded a grant from the Office of Dietary Supplements (NIH) to study the role of vitamin D and methylation in breast cancer risk. This work is beginning now, with specimens being pulled for assay.

这项由Komen资助的研究招募了患有乳腺癌的女性，一个未受影响的姐妹已经作为姐妹研究队列的一部分进行了研究，如果可以的话，他们的父母。我们将联合收割机将他们的数据与现在从他们未受影响的姐妹篇（以前加入姐妹研究）收集的DNA和环境数据以及从他们父母收集的唾液DNA相结合。 我们正在使用一个核心家庭为基础的方法来研究遗传和环境因素参与了乳腺癌的发病。该研究通过利用姐妹研究（Dale Sandler，PI）已经到位并顺利运行的基础设施，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和验证所有这些突发病例的诊断。 对这些病例的随访（与姐妹研究中的新病例合并后）也将使我们能够确定影响治疗后健康的环境，临床和遗传因素。 基因变异的病例-亲本分析受到保护，不会因遗传遗传的混淆而产生偏倚，并且还允许检测母体介导的遗传效应和亲本起源（印记）效应。 在拟议的研究中，参与的受影响姐妹篇每个人都完成了一个计算机辅助电话访谈，就像他们的姐妹在姐妹研究中完成的那样，提供了有关个人暴露、生殖史和过去职业暴露的信息。 环境影响将通过受影响和未受影响姐妹篇的配对比较来识别。 将采用新的统计方法评估基因-暴露相互作用。 总之，两姐妹研究利用正在进行的姐妹研究，建立一个具有成本效益的，强大的，统计独立的研究乳腺癌。 与遗传变异和环境因素的综合影响有关的发现可以在姐妹研究中复制。 我们已完成研究入组。 通过纳入一些来自姐妹研究的新诊断的新发病例，我们招募了近1500例病例，提供问卷数据和DNA。 我们还招募了1403名提供DNA的父母。这项工作是在执行局支助服务合同的协助下完成的。我们获得了资助机构的许可（苏珊G。科门的治疗）的一个无成本的扩展和重新定向的钱原本打算用于候选基因的方法，而不是进行全基因组关联研究（GWAS），使用Illumina OmniExpress加外显子组芯片。通过与遗传疾病研究中心的合同进行，这个基因分型项目（通过估算增加）在这些家庭中产生了超过2000万个SNP。 我们还参与了GAME-ON联盟，这项工作再次通过CIDR提供了基于新开发的癌基因芯片的额外基因型数据。我们正在使用这些数据来寻找年轻人发病乳腺癌的基因-环境因果因素。 通过将两个姐妹病例与姐妹研究中出现的事件病例相结合，我们还将能够研究与治疗后健康无复发生存率相关的复杂因素。 偏头痛病史和乳腺癌风险之间可能存在联系，我们使用两姐妹研究的数据进行了与该问题相关的分析。 我们区分了倾向于在月经周期的特定时间发生的偏头痛和那些不遵循月经模式的偏头痛。 总的来说，偏头痛和乳腺癌发病风险之间没有关系。 该文件目前正在审查中。 在与我的新博士后Katie奥布莱恩的合作中，我们考虑了激素替代疗法（HRT）的暴露史和年轻发病乳腺癌的风险，使用了两姐妹研究的数据。 在进行这一分析时需要克服的一个复杂问题是与2002年发表的妇女健康倡议试验结果有关的出生队列效应，该试验发现雌激素/孕激素替代疗法会增加患乳腺癌和其他疾病的风险。由于该报告对临床实践产生了影响，在2002年之前经历更年期的妇女比那些在这些研究结果发表后经历更年期的姐妹篇更有可能使用HRT。 因为在双姐妹研究中，对照姐妹篇往往比病例组的姐妹年长，这种出生队列效应意味着对照组更有可能接受激素替代疗法。 为了调整这种不同的暴露机会，我们进行了倾向评分分析，其中我们使用来自姐妹研究的数据来模拟暴露的可能性，并使用来自两个姐妹研究的数据将这些倾向概率应用于logistic模型。目前正在审查由此产生的文件。 正在审查的第二篇论文比较了50岁以下诊断为乳腺导管原位癌和浸润性乳腺癌的女性的风险因素概况，再次使用来自两姐妹研究的数据。 这项工作是与我们的本科生暑期实习生从去年夏天，珍妮孙。 在去年夏天与实习生丹尼斯·惠兰（Denis Whelan）一起工作时，我们考虑了自我报告的与乳腺癌风险因素有关的饮食失调史，并描述了与后来的身体习惯和生殖事件的关联。 对基因数据的分析正在进行中。 我们申请并获得了膳食补充剂办公室（NIH）的资助，以研究维生素D和甲基化在乳腺癌风险中的作用。 这项工作现在已经开始，正在抽取标本进行化验。