A pooled investigation of circulating adiponectin and multiple myeloma

We plan to compete for NCI Intramural Research Program funds (FY 2013) to support the proposed project.

Multiple myeloma (MM) is a highly fatal lymphoid malignancy, with five-year relative survival in the United States of less than 40% (1). Obesity has been consistently associated with increased MM risk (2), although the specific biologic mechanisms have yet to be elucidated. Alterations in circulating levels of adipokines, polypeptide hormones secreted by adipose tissue, have been proposed as a potential mechanism through which obesity contributes to myelomagenesis. The most abundant adipokine, adiponectin, is mainly produced by visceral adipose tissue (3); it has important anti-inflammatory and insulin-sensitizing properties, and circulating levels are negatively correlated with obesity (3-5). The ratio of the oligomeric forms of adiponectin may affect insulin sensitivity, with higher concentrations of high-molecular-weight (HMW) adiponectin protecting against insulin resistance (4, 6).

In a recent nested case-control study conducted within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (174 cases, 348 controls), we observed statistically significant inverse associations with multiple myeloma risk for pre-diagnostic plasma levels of total adiponectin (highest quartile vs. lowest: odds ratio 0.49, 95% confidence interval 0.26-0.93; Ptrend = 0.03) and HMW adiponectin (0.44, 0.23-0.85; Ptrend = 0.01) (7). These findings were similar among men and women, and the associations remained after adjustment for body mass index and restricting to matched sets with ≥8 years from blood collection to case diagnosis.

These findings suggest that adiponectin may play a role in obesity-related myelomagenesis, although it is essential for this association to be replicated in other study populations before meaningful causal inferences can be drawn. To that end, we propose to conduct a pooled investigation of circulating adiponectin and MM within the NCI Cohort Consortium.

References
1) ACS. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society, 2010.
2) Wallin A, Larsson SC. Body mass index and risk of multiple myeloma: a meta-analysis of prospective studies. Eur J Cancer 2011;47(11):1606-15.
3) Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010;61:301-16.
4) Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006;83(2):461S-5S.
5) van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 2009;18(10):2569-78.
6) Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and and immunity. Nat Rev Immunol 2006;6(10):772-83.
7) Hofmann JN,Liao LM, Pollak MN, Tao Y, Baris D, Andreotti G, Lan Q, Landgren O, Rothman N, Purdue MP. A prospective study of circulating adipokine levels and risk of multiple myeloma. Manuscript in preparation.

Our goal is to investigate whether, as previously observed in PLCO, elevated levels of total and high-molecular-weight adiponectin are associated with reduced risk of multiple myeloma (MM). We hypothesize that adiponectin effects at least partly mediate the association between obesity and MM. Obese individuals typically have lower serum levels of adiponectin, which may protect against MM through its anti-inflammatory and insulin-sensitizing properties.

1) Investigate the association between circulating total and high-molecular-weight adiponectin and multiple myeloma risk.
2) Explore whether these associations differ by sex, race (restricted to white subjects), age, body mass index, and with time from blood collection to case diagnosis.
3) Explore through mediation analyses whether adjustment for adiponectin attenuates the BMI-myeloma association.

We propose to include multiple myeloma cases and individually-matched controls (1:2 ratio) with pre-diagnostic serum or plasma (100ul needed). Conditional models will be used to estimate adiponectin-myeloma associations. With 400 cases and 800 controls, we will have ≥80% power to detect an OR ≤0.63 comparing the highest and lowest quartiles (two-sided test, alpha=0.05).

A prospective design is essential to addressing this question in order to minimize the potential of bias due to disease-induced changes in analyte levels. A consortial approach is necessary to achieve adequate statistical power given the rarity of multiple myeloma (annual incidence 5.8 cases per 100,000: SEER-18, 2005-2009).

10

Multiple myeloma case-control status

Not applicable.

Age at blood collection, sex, race, body mass index at enrollment (and at earlier ages if available), specimen type, specimen collection date, specimen collection time, fasting status, length of follow-up from specimen collection to case diagnosis.

Yes

No special processing is required. Serum or plasma is fine for this project.