Prospective evaluation of IGF and IL-6 Dysregulation and Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是一种恶性肿瘤，生存率低，没有已知的可改变的危险因素。因此，需要前瞻性研究来表征MM的病因，以制定预防策略。实验室研究已经描述了IGF-1和IL-6通路在MM发病机制中的重要作用。通过一项包括至少498例MM病例和996例对照的前瞻性生物标本的合作研究，我们具有独特的优势，可以首次研究IGF-1和IL-6在MM病因学中的作用。本应用程序解决以下具体假设：胰岛素样生长因子(IGF)-1途径a.循环中IGF-1、IGF结合蛋白(IGFBP)-1、IGFBP-3、酸不稳定亚基（ALS）和C-肽水平与MM发病率增加有关b. IGF-1、IGFBP-1、-2和-3、IGF- i受体（IGF- ir）和胰岛素受体底物(IRS)-1和-2基因的特异性多态性和单倍型与MM 2风险增加有关。白细胞介素(IL)-6上调和b细胞刺激a.血浆中IL-6、slL-6R和c反应蛋白水平与MM呈正相关。b. IL-6通路中的特定多态性和单倍型增加MM的风险。我们将对来自9个大型队列的MM病例进行汇总前瞻性研究，这些队列具有存档的、前瞻性获得的血浆和DNA标本。妇女健康倡议、护士健康研究、卫生专业人员随访研究、妇女健康研究、医生健康研究和新加坡华人队列研究。在NCI的校内项目中，我们有PLCO和ATBC来自澳大利亚，我们有墨尔本合作队列。我们将采用前瞻性嵌套病例对照设计来检查血清学和遗传生物标志物与多发性骨髓瘤的关联。在二次分析中，我们将探讨给定的IGF-1或il -6相关标志物与多发性骨髓瘤的关联是否因已知或建议的危险因素（包括年龄、性别、MGUS状态或体重指数）的状态而变化。每个队列由一名高级研究员（或研究PI）代表，他将监督该研究的病例对照鉴定，然后参与数据分析的计划和解释。这个团队由dr。Colditz和Anderson的研究得到了一位高级统计学家（Rosner博士）和一位研究主任（Birmann博士）的支持，Birmann博士的部分资金来自K奖。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a malignancy with poor survival and without known modifiable risk factors. Thus, prospective studies are needed to characterize the etiology of MM to inform the development of prevention strategies. Laboratory research has described important roles for the IGF-1 and IL-6 pathways in MM pathogenesis. With a collaborative study that includes a total of at least 498 MM cases and 996 controls with prospectively collected biospecimens, we are uniquely situated to conduct the first examination of the role of IGF-1 and IL-6 in MM etiology. This application addresses the following specific hypotheses: 1. Insulin-like growth factor (IGF)-1 pathway a. Circulating levels of IGF-1, IGF binding protein (IGFBP)-1, IGFBP-3, acid labile subunit (ALS), and C- peptide are related to increased incidence of MM b. Specific polymorphisms and haplotypes in the IGF-I, IGFBP-1,-2, and -3, IGF-I receptor (IGF-IR), and insulin receptor substrate (IRS)-1 and -2 genes are associated with increased risk of MM 2. Interleukin (IL)-6 upregulation and B-cell stimulation a. Plasma levels of IL-6, slL-6R, and C-reactive protein are positively associated with MM. b. Specific polymorphisms and haplotypes in the IL-6 pathway increase risk of MM. We will conduct pooled prospective studies with incident cases of MM from nine large cohorts with archived, prospectively acquired plasma and DNA specimens: the Women's Health Initiative, the Nurses' Health Study, the Health Professionals' Follow-up Study, the Women's Health Study, the Physician's Health Study, and the Singapore Chinese Cohort. From the intramural program at NCI, we have PLCO and ATBC and from Australia, we have the Melbourne Collaborative Cohort. We will utilize a prospective nested case- control design to examine the associations of the serologic and genetic biomarkers with incident MM. In secondary analyses, we will explore whether the association of a given IGF-1- or IL-6-related marker with MM varies by status of known or suggested risk factors, including age, gender, MGUS status, or body mass index. Each cohort is represented by a senior investigator (or study PI) who will oversee the case-control identification from that study, and then participate in the planning and interpretation of data analyses. The team is led from by Drs. Colditz and Anderson and is supported by a senior statistician (Dr. Rosner) and a study director (Dr. Birmann) who is funded, in part, through a K award.