The Two Sister Study

两姐妹研究招募了患有年轻乳腺癌的女性，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，如果有的话，还包括她们的父母。我们将他们的数据与现在从他们未受影响的姐妹(之前加入姐妹研究)收集的DNA和环境数据以及从他们父母那里收集的基于唾液的DNA结合起来。我们正在使用以核心家庭为基础的方法来研究与年轻乳腺癌有关的遗传和环境因素。这项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。对这些病例的跟踪(在与Sister研究中的新病例合并后)也将使我们能够识别影响治疗后健康的环境、临床和遗传因素。 对基因变异的病例-亲本分析受到保护，不会因遗传遗传造成的混淆而产生偏见，还允许检测母体介导的遗传效应和亲本(印记)效应。在这项研究中，参与研究的每个受影响的姐妹都完成了一次计算机辅助电话采访，就像她们的姐妹为姐妹研究完成的那样，提供了关于个人暴露、生育史和过去职业暴露的广泛信息。非遗传效应可以通过对受影响的姐妹和未受影响的姐妹进行配对比较来识别。 通过包括Sister研究中的一些新诊断的年轻发病病例，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EB支助服务合同的协助下完成的。我们从资助机构(Susan G.Komen for the Cure)获得了免费延期的许可，并将原本用于候选基因方法的资金重新定向，转而使用Illumina OmniExpress Plus Exome芯片进行全基因组关联研究(GWAS)。通过与遗传病研究中心的一项合同进行的这项基因分型项目(通过注入补充)在这些家庭中产生了2000多万个SNP。这些数据已通过DBGaP向公众公布，并已被其他调查人员多次下载。我们还参加了GAME-On联盟，这项工作提供了基于新开发的Onco阵列芯片的额外基因数据，也是通过CIDR。我们正在使用这些数据来寻找年轻乳腺癌发病的基因与环境的因果因素。通过将两个姐妹病例与姐妹研究中出现的那些事件病例相结合，我们还将能够研究与治疗后健康无复发生存相关的因素的复合体。我们现在已经发表了一篇关于全基因组分析的论文，既包括母系基因分析，也包括女儿遗传基因分析。 人们对偏头痛病史和乳腺癌风险之间的可能关系很感兴趣，我们使用两姐妹研究的数据进行了与这个问题相关的分析。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。总体而言，偏头痛与年轻发病乳腺癌的风险之间没有关系，但患有偏头痛并患有乳腺癌并有月经相关偏头痛病史的女性更有可能患上激素阳性肿瘤。 在2014年夏天与实习生丹尼斯·惠兰(Denis Whelan)合作的工作中，我们认为，与人口统计和其他原因有关的自我报告的年轻起病饮食障碍史，还认为生活中任何阶段的饮食障碍都可能是乳腺癌的风险因素。我们还描述了与后来的身体习性和生殖结果之间的关系。这项工作产生了两篇论文，一篇表明进食障碍史与乳腺癌之间的关系不大，另一篇则表明与进食障碍有关的生殖问题。 与疾病控制和预防中心的研究人员合作的一个正在进行的项目正在研究Sister研究的参与者，以确定他们对癌症筛查风险和使用的信念，并研究乳腺癌幸存者，以了解他们的生活、健康和前景因乳腺癌的诊断而发生了怎样的变化。 个别项目发现有证据表明，妊娠期糖尿病、腰围过大和睡眠障碍可能与乳腺癌风险有关。 在过去的一年中，可能最重要的项目是我们的工作，表明在测量的5年内，维生素D水平的升高与乳腺癌风险的降低有关。在第二篇正在修改的论文中，我们发现了基因与维生素D的相互作用，特别是与维生素D受体相关的遗传变异。

The Two Sister 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 have combined 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). 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 this study, the participating affected sisters each completed a computer-assisted telephone interview like the one their sister completed for the Sister Study, providing extensive information about personal exposures, reproductive history, and past occupational exposures. Nongenetic effects are identifiable through a paired comparison of affected and unaffected sisters. With augmentation by including some newly diagnosed young-onset cases from the Sister Study we 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 (augmented by imputations) generated more than 20 million SNPs on these families. These data have been made publically available through dbGaP and have been downloaded many times by other investigators. We are also participating in the GAME-ON consortium, and this effort has provided additional genotype data based on the newly developed Onco-array chip, 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. We have now published a paper reporting on the genome wide analyses, both for the maternal genotype and for the daughter-inherited genotype. 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, but women with migraine who develop breast cancer and have a history of a menstrually-related migraine pattern are more likely to develop a hormone positive tumor. In work originated in the summer of 2014 with an intern, Denis Whelan, we considered self-reported history of a young-onset eating disorder in relation to demographic and other causes and also considered eating disorders at any stage of life as possible risk factors for breast cancer. We also described associations with later body habitus and reproductive outcomes. Two papers resulted from that work, one showing little relationship between a history of an eating disorder and breast cancer and one showing reproductive problems in association with an eating disorder. An ongoing project collaborative with investigators at the Centers for Disease Control and Prevention is studying the participants in the Sister Study to ascertain their beliefs about risk and use of cancer screening and also studying the survivors of breast cancer to learn how their lives, their health and their outlook have been changed by the diagnosis of breast cancer. Individual projects have found evidence that gestational diabetes, large waist circumference, and sleep disturbance, may be associated with risk of breast cancer. Possibly the most important of the projects in this past year was our work showing that elevated levels of vitamin D are related to reduced risk of breast cancer within 5 years of measurement. In a second paper, now undergoing revision, we found gene-by-vitamin D interaction, particularly with genetic variants related to the vitamin D receptor.