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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology of Cancer Study Section (EPIC)
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Mechanic, Leah E
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Washington University
Schools of Medicine
Saint Louis
United States
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Birmann, Brenda M; Andreotti, Gabriella; De Roos, Anneclaire J et al. (2017) Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC). Cancer Epidemiol Biomarkers Prev 26:876-885
Santo, Loredana; Teras, Lauren R; Giles, Graham G et al. (2017) Circulating resistin levels and risk of multiple myeloma in three prospective cohorts. Br J Cancer 117:1241-1245
Matthews, Geoffrey M; de Matos Simoes, Ricardo; Dhimolea, Eugen et al. (2016) NF-?B dysregulation in multiple myeloma. Semin Cancer Biol 39:68-76
Costas, Laura; Lambert, Brice H; Birmann, Brenda M et al. (2016) A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium. Cancer Epidemiol Biomarkers Prev 25:217-21
Hofmann, Jonathan N; Birmann, Brenda M; Teras, Lauren R et al. (2016) Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals. Cancer Res 76:1935-41
Birmann, Brenda M; Barnard, Mollie E; Bertrand, Kimberly A et al. (2016) Nurses' Health Study Contributions on the Epidemiology of Less Common Cancers: Endometrial, Ovarian, Pancreatic, and Hematologic. Am J Public Health 106:1608-15
Varga, Cindy; Xie, Wanling; Laubach, Jacob et al. (2015) Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. Br J Haematol 169:843-50
Mitsiades, Constantine S (2015) Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway. J Clin Oncol 33:782-5
Birmann, Brenda M; Giovannucci, Edward L; Rosner, Bernard A et al. (2014) Regular aspirin use and risk of multiple myeloma: a prospective analysis in the health professionals follow-up study and nurses' health study. Cancer Prev Res (Phila) 7:33-41
Gatt, Moshe E; Takada, Kohichi; Mani, Mala et al. (2013) TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity. Br J Haematol 162:210-20

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