The Two Sister Study

这项由Komen资助的研究招募了患有乳腺癌的女性，以及她们的父母。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。 我们将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（Dale Sandler，PI）。 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。 这些病例的随访（通过姐妹研究）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，拟议的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，统计学独立的研究乳腺癌。 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。我们最近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，这个基因分型项目应该在这些家庭中提供超过100万个SNP。目前正在进行最后的DNA提取，基因分型将在未来几个月内完成。 我们希望利用这些数据来寻找年轻发病乳腺癌的基因-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。 今年，我们与博士后费春元（音）一起发表了两篇基于双姐妹研究的论文。 首先，我们研究了刺激排卵生育药物的暴露史。 这些暴露具有激素效应，引起了人们对乳腺癌的担忧，但文献报道好坏参半。 我们认识到，如果怀孕，暴露是不同的，因为激素水平在怀孕的前三个月保持升高，可能影响乳房组织的重塑。 根据条件logistic回归模型，与未接触者相比，接触者的风险降低，但如果治疗导致怀孕，则失去了明显的保护作用。 我们有另一篇关于有更年期相关症状史的妇女所享有的明显保护的论文。 我们有几篇论文与姐妹研究有关。其中一项已被《国家癌症研究所杂志》暂时接受，该研究使用基线时收集的血液评估了基因组中约27，000个CpG位点的甲基化，并将这些结果与乳腺癌的后期发展联系起来。 甲基化状态是癌症风险的预测因子。

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.