The Two Sister Study

两姐妹研究

• 批准号: 9550132
• 负责人: Clarice Weinberg
• 金额: $ 50.49万
• 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/9550132
• 关键词: Affect; Aftercare; Age; Authorization documentation; Belief; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer survivor; Cadmium; Candidate Disease Gene; Centers for Disease Control and Prevention (U.S.); Cohort Studies; Complex; Computer Assisted; Contract Services; Contracts; DNA; Data; Databases; Daughter; Detection; Diagnosis; Disease; Eating Disorders; Enrollment; Environment; Environmental Risk Factor; Family; Funding; Funding Agency; Genes; Genetic; Genetic study; Genotype; Gestational Diabetes; Goals; Health; Hormones; Individual; Inherited; Internships; Joints; Learning; Life; Link; Measurement; Mediating; Medical Genetics; Menstrual cycle; Migraine; Neurocognitive; Newly Diagnosed; Nuclear Family; Occupational Exposure; Outcome; Paired Comparison; Paper; Parents; Participant; Patient Self-Report; Pattern; Predictive Factor; Prospective Studies; Publishing; Questionnaires; Recording of previous events; Recruitment Activity; Recurrence; Reporting; Reproductive History; Research; Research Infrastructure; Research Personnel; Risk; Role; Saliva; Screening for cancer; Secure; Serum; Sister; Sleep disturbances; Specimen; Structure of nail of toe; Surveys; Survivors; Telephone Interviews; Time; Trace Elements; Vitamin D; Vitamin D3 Receptor; Vitamins; Woman; Work; base; breast cancer diagnosis; cancer therapy; cohort; college; cost; database of Genotypes and Phenotypes; design; disorder prevention; exome; experience; family structure; follow up assessment; follow-up; genetic variant; genome wide association study; genome-wide analysis; imprint; interest; malignant breast neoplasm; non-genetic; novel; outcome forecast; permissiveness; reproductive; tumor; validation studies; waist circumference

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.

这两项姐妹研究招募了患有年轻乳腺癌的妇女，这是一个未受影响的姐姐，作为姐妹研究队列的一部分，并在有可能的话的时候是父母。我们已经将他们的数据与目前从未受影响的姐妹（以前加入姐妹研究的姐妹）中收集的DNA和环境数据结合在一起，并从父母那里收集了基于唾液的DNA。 我们正在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。这些病例的随访（在姐妹研究中与新病例合并后）还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。 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。 在这项研究中，参与受影响的姐妹们每个人都完成了计算机辅助的电话访谈，就像他们的姐姐完成了姐妹研究的那样，提供了有关个人暴露，生殖历史和过去职业曝光的广泛信息。 通过对受影响和未受影响的姐妹的配对比较，可以识别非核效应。 通过包括一些新诊断的年轻发病案例，我们招募了近1500例，提供了调查表数据和DNA。 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。我们获得了资助机构（Susan G. Komen进行治疗）的许可，以进行无成本扩展，并使用Illumina Omniexpress Plus Omniexpress Plus Exome Chip，将最初用于候选基因方法的资金重定向。通过与遗传性疾病研究中心的合同实现的基因分型项目（归类增强）为这些家庭产生了超过2000万个SNP。 这些数据已通过DBGAP公开获得，并已由其他调查人员下载了很多次。我们还参加了游戏联盟，这项工作再次通过CIDR提供了基于新开发的Onco-Array芯片的其他基因型数据。我们正在使用这些数据来找到YOUNG乳腺癌的基因因果因素。 通过将两个姐妹病例与姐妹研究中产生的事件案例相结合，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。现在，我们已经发表了有关母体基因型和daughter依的基因型的基因组广泛分析的论文报告。 人们对偏头痛病史和乳腺癌风险之间的可能关系有兴趣，我们使用两项姐妹研究的数据进行了与该问题有关的分析。 我们区分了倾向于在月经周期的特定时间发生的偏头痛与未遵循月经模式的偏头痛。 总体而言，偏头痛与年轻乳腺癌的风险之间没有关系，但是患有乳腺癌且具有月经相关偏头痛病史的偏头痛女性更有可能发展为激素阳性肿瘤。 在2014年夏季的工作中，我们认为与人口统计学和其他原因有关的年轻发作饮食障碍的历史自我报告的历史，并在生活的任何阶段都认为饮食失调是乳腺癌的危险因素。 我们还描述了与后来的身体习惯和生殖结果的关联。这项工作产生了两篇论文，一篇论文显示出饮食失调症和乳腺癌的病史之间的关系很小，另一篇是与饮食失调有关的生殖问题。 与疾病控制和预防中心的研究人员进行的一项正在进行的项目合作正在研究姐妹研究的参与者，以确定他们对癌症筛查的风险和使用的信念，并研究乳腺癌的幸存者，以了解他们的生活，健康和外观如何通过乳腺癌的诊断而改变。 各个项目发现的证据表明，妊娠糖尿病，大腰围和睡眠障碍可能与患乳腺癌的风险有关。 过去一年中，最重要的项目可能是我们的工作表明，维生素D水平升高与测量5年内乳腺癌的风险降低有关。在现在正在进行修订的第二篇论文中，我们发现了基因相互作用，尤其是与与维生素D受体有关的遗传变异。