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Prospective evaluation of IGF and IL-6 dysregulation and multiple myeloma

Principal Investigator
Name
Mark Purdue
Degrees
-
Institution
NCI, DCEG, OEEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2009-0506
Initial CDAS Request Approval
Jun 10, 2009
Title
Prospective evaluation of IGF and IL-6 dysregulation and multiple myeloma
Summary
The etiology of multiple myeloma (MM) is poorly understood despite its sharply increasing incidence in persons age >50 years and low (30%) 5-year survival. Identification of modifiable risk factors is thus a priority for improving the health of middle-aged and older women and men. The recently reported association of MM with obesity may be related to dysregulation of insulin-like growth factor (IGF)-1 and/or interleukin (IL)-6 pathways, which are important to MM pathogenesis. To evaluate this hypothesis, a pooling project within the Cohort Consortium is being developed to investigate the association with MM risk for genetic and serologic markers of IGF-1 and IL-6 dysregulation. The data will be obtained from nine large cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, the Women's Health Study, the Women's Health Initiative, the American Cancer Society Cancer Prevention Study II cohort, the Singapore Chinese Cohort, the Melbourne Collaborative Cohort, and two NCI Intramural cohorts–the PLCO and ATBC trials. This project will involve an estimated total sample size of 560 cases and 1120 controls. Plasma markers to be measured include IGF-1, IGF binding protein-3, C-peptide, IL-6, soluble IL-6 receptor, and C-reactive protein. Single nucleotide polymorphisms (SNPs) summarizing common genetic variation in 10 IGF & IL6 pathway genes (IGF1, IGF1R, IGFBP1, IGFBP2, IGFBP3, IRS1, IRS2, IL6, IL6R, and gp130) will be genotyped.
Aims

Briefly, MM is the second most common hematopoietic malignancy diagnosed in the United States (US) [1]; the American Cancer Society projects that 19,970 new cases and 10,690 deaths from MM will occur in 2008 [2]. Obesity has been positively associated with MM risk [3-6], but the biologic mechanism underlying this association is not known. Insulin-like growth factor (IGF)-I and interleukin (IL)-6 are important in the pathogenesis of MM [7-12]. It is plausible that dysregulation of IGF-1 and/or IL-6, or variation in genes that encode molecules important to signaling by IGF-1 and/or IL-6, is associated with risk of MM. We will examine the association of serologic markers of IGF-1 and IL-6 upregulation, and of common variants in IGF-1- and IL-6-related genes, with incident MM. With the combined nested case-control data we will address the following specific hypotheses: 1. IGF-1 pathway a. Plasma levels of total IGF-1, IGF binding protein (IGFBP)-3, and C-peptide are associated with MM incidence. b. Common SNPs and haplotypes in IGF pathway genes (IGF1, IGF1R, IGFBP1, IGFBP2, IGFBP3, IRS1, IRS2), identified through the NCI Cohort Consortium and/or through public database and literature searches, are associated with susceptibility to MM. 2. IL-6 upregulation and B-cell stimulation. a. Plasma levels of IL-6, sIL-6R, and C-reactive protein (CRP) are positively associated with MM b. Variation in genes encoding IL-6-related signaling molecules, including IL6, IL6R, and gp130, are associated with susceptibility to MM

Collaborators

Ola Landgren (NCI, DCEG)
Mark Purdue (NCI, DCEG)
Nathaniel Rothman (NCI, DCEG)

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