AS207 - IGF and multiple myeloma

Investigator Names and Contact Information

Graham Colditz (colditzg@wustl.edu)

Introduction/Intent

Introduction/Intent

The etiology of multiple myeloma (MM) is poorly understood despite its sharply increasing incidence in persons age ³50 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. We propose to evaluate this hypothesis in a nested case-control study, using archived plasma and DNA biospecimens from 151 confirmed MM cases and 302 matched controls in the WHI. We will combine the WHI participants' data with those from 100 cases and 200 controls ascertained in three large Harvard-based cohort studies. We will utilize conditional logistic regression to estimate the association of plasma IGF-1, IGF binding protein 3, acid-labile subunit, C-peptide, IL-6, soluble IL-6 receptor, and C-reactive protein with MM. We will also examine the association of unique haplotypes of 5 IGF-related genes with MM, using haplotypes identified by the Cohort Consortium. We will thus be the first to explore etiologic associations of plasma levels of IGF-1- and IL-6-related markers and of IGF gene variability with MM.

Aims

Multiple myeloma (MM) is the second most common hematopoietic malignancy diagnosed in the United States (US), comprising approximately 1% of all cancers or an average of 14,600 new cases per year [1]. In contrast to recent advances in the treatment of MM, the etiology of this disease remains poorly understood, particularly with regard to modifiable risk factors. Obesity has been positively associated with MM incidence and mortality in large population-based studies [2-4], but the biologic mechanism underlying this association is not known. Laboratory studies suggest that insulin-like growth factor (IGF)-1 acts as both a proliferative and an antiapoptotic agent in MM cell lines [5,6], and that IGF-1 modulates the migration of MM cells [7]. Also, inhibition of the IGF-1 receptor (IGF-1R) was associated with pleiotropic antitumor activity in vitro and in mouse models [8]. In addition, the condition of obesity is now recognized to be a state of chronic inflammation [9]. Of note, the pro-inflammatory cytokine interleukin-6 (IL-6) stimulates B-cell differentiation, is secreted by bone marrow stromal cells and by adipose tissue, and has potent growth-promoting effects on MM tumor cells [10-12]. Plasma IL-6 and C-reactive protein (CRP), an acute phase protein indicative of inflammation and of IL-6 activity, are elevated in obese persons [9]. Higher plasma levels of IL-6 and of the soluble receptor (sIL-6R) have also been reported in MM patients and in persons with monoclonal gammopathy of uncertain significance (MGUS), an established risk factor for MM [12].

Thus, the studies we propose to conduct within the Women's Health Initiative (WHI) blood cohort utilize a nested case-control design to examine the associations of serologic biomarkers of IGF-1 and IL-6 upregulation, and of IGF-1-related gene haplotypes, with incident MM. The data obtained from WHI subjects will be pooled with those acquired from comparable studies within three other large cohorts at Harvard University with archived plasma and DNA specimens: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Women's Health Study. The pooled study sample will have at least 250 cases of myeloma. With the combined nested case-control data we will address the following specific hypotheses:

1. IGF-1 pathway
   • Plasma levels of total IGF-1 are positively associated with MM, whereas plasma IGF binding protein type 3 (IGFBP-3) is inversely associated with MM.
   • Total IGF-1 to IGFBP-3 ratio is positively associated with MM.
   • Plasma acid-labile subunit (ALS) is positively associated with MM.
   • Plasma C-peptide is positively associated with MM.
   • Unique IGF pathway gene haplotypes identified through the NCI Cohort Consortium predict risk of MM.
2. IL-6 upregulation and B-cell stimulation
   • Plasma levels of IL-6 and sIL-6R are positively associated with MM.
   • Plasma C-reactive protein (CRP), a marker of IL-6 activity and of inflammation, is positively associated with MM.
3. IL-6 upregulation and B-cell stimulation
   • Plasma levels of IL-6 and sIL-6R are positively associated with MM.
   • Plasma C-reactive protein (CRP), a marker of IL-6 activity and of inflammation, is positively associated with MM.

Results/Findings

Some of the publications related to this ancillary study are:

Ms1164 - Birmann BM, Neuhouser ML, Rosner B, Albanes D, Buring JE, Giles GG, Lan Q, Lee IM, Purdue MP, Rothman N, Severi G, Yuan JM, Anderson KC, Pollak M, Rifai N, Hartge P, Landgren O, Lessin L, Virtamo J, Wallace RB, Manson JE, Colditz GA. Pre-diagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium. Blood. 2012 Dec 13;120(25):4929-37. Epub 2012 Oct 16

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.