Posted on June 20, 2018
by Victoria Fisher, M.P.H.
Tenure-track investigator Jonathan Hofmann, Ph.D., M.P.H., has established a research program in the Occupational and Environmental Epidemiology Branch focused on the role of agricultural exposures in the etiology of multiple myeloma and other cancers, and on understanding the biological mechanisms that influence the development and progression of multiple myeloma.
Multiple myeloma is a cancer that affects plasma cells, a type of white blood cell that produces antibodies to fight infection and disease. Despite recent advances in treatment, the prognosis for multiple myeloma remains unfavorable, with an estimated five-year relative survival rate of approximately 50 percent. Although it is a rare cancer, African Americans are twice as likely to be diagnosed compared to Americans of European ancestry; the reasons for this disparity and the etiology of this malignancy remain unclear.
A unique feature of multiple myeloma is that it is almost always preceded by a largely asymptomatic condition called monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have about a one-percent per year chance of progressing to multiple myeloma.
In addition to MGUS and race/ethnicity, other factors known to increase a person’s likelihood of developing this cancer include increasing age, male sex, severe immune dysregulation, and obesity.
Dr. Hofmann and colleagues are building on evidence that certain agricultural exposures may also influence the risk of multiple myeloma. An excess of this cancer has been consistently observed among farmers and other agricultural workers in studies worldwide over the past 30 years. However, there is little clarity about the magnitude of the risk, or the specific exposures that contribute to these observations.
Dr. Hofmann is leading a major molecular epidemiologic investigation within the Agricultural Health Study (AHS)—known as the Biomarkers of Exposure and Effect in Agriculture (BEEA) study—to explore the relationships between agricultural exposures and intermediate biomarkers related to multiple myeloma and other cancers.
BEEA launched in 2010 and over the past several years has enrolled nearly 1,700 pesticide applicators and 200 controls. “We’ve just completed the field data collection effort,” Dr. Hofmann said. “One of the main questions we’re trying to address in BEEA is whether there is also an excess risk of MGUS among this population.”
During home visits, BEEA participants were interviewed about recent agricultural exposures and provided blood, urine, buccal cell, and house dust samples. Investigators selected individuals who had completed all of the previous AHS questionnaires, so they have a comprehensive lifetime history of occupational exposures to pesticides and other agricultural exposures. In addition, they chose participants over the age of 50, in part because MGUS is rarely detected among younger individuals.
Dr. Hofmann noted, “the updated information and biospecimens, coupled with the lifetime history of pesticide use obtained within the AHS, provide an unprecedented opportunity to conduct mechanistic studies of important chemicals used in agriculture and other settings that are linked to cancer.” He and collaborators are now poised to take advantage of this important resource.
In a previous analysis of AHS samples from a separate, smaller sub-study, Dr. Ola Landgren, now at Memorial Sloan-Kettering Cancer Center, and colleagues observed a two-fold excess risk of MGUS compared to a demographically similar population. Dr. Hofmann is following up and extending this important finding within BEEA by characterizing the prevalence of MGUS and investigating associations with specific pesticides and other agricultural exposures with almost three times the number of samples as the previous analysis.
In addition, he and postdoctoral fellow Joe Shearer, Ph.D., M.P.H., are conducting a special effort within BEEA to investigate hematologic alterations among participants with serial blood samples collected before and after exposure to permethrin, a widely-used insecticide that has been associated with an increased risk of multiple myeloma in the AHS. “We’re looking at select immunologic markers that have previously been associated with multiple myeloma, and we’re trying to understand whether these markers are altered after permethrin exposure,” Dr. Hofmann said.
Agricultural exposures—including pesticides, bioaerosols such as endotoxin (a component of the cell wall of gram-negative bacteria), diesel exhaust, and viral and bacterial exposures related to livestock and poultry—have been associated with risk of various other cancers, although the biological mechanisms underlying these associations are generally not well understood.
Dr. Hofmann and colleagues have published two papers reporting initial findings from BEEA, including the first comprehensive investigation of lung cancer-related immune markers among endotoxin-exposed farmers. Farmers raising hogs in confined facilities are often highly exposed to endotoxin, which provokes an acute inflammatory response. Furthermore, occupational exposure to endotoxin has been consistently associated with a reduced risk of lung cancer. In this new study, Dr. Hofmann and colleagues found that circulating levels of a macrophage-derived chemokine (MDC/CCL22), a chemokine that has been prospectively linked to lung cancer development, were significantly reduced among hog farmers; several other endotoxin-related immunological markers were elevated. These findings provide insights into the potential mechanisms of action through which endotoxin prevents lung carcinogenesis.
In the second paper, led by postdoctoral fellow Catherine Lerro, Ph.D., investigators observed associations between long-term occupational exposure to certain pesticides, thyroid hormone levels, and subclinical hypothyroidism.
In the long-term, BEEA will serve as a biorepository for cross-sectional molecular epidemiologic studies to elucidate the biological mechanisms underlying associations between agricultural exposures and various cancers or other chronic diseases.
“While much of my current work is focused on multiple myeloma and MGUS, we plan to look at many different types of exposures and health outcomes,” Dr. Hofmann said. “The data and biospecimens collected in BEEA will serve as a critical resource for future studies.” Investigators will evaluate targeted hypotheses and broader, agnostic questions using selected “omic” platforms related to pesticides and other agricultural exposures.
To date, the only established modifiable risk factor for multiple myeloma is obesity; Dr. Hofmann has contributed to our understanding that excess body weight throughout adult life influences risk. He is tapping a number of existing epidemiologic cohorts to look for biomarkers associated with obesity and both the development and progression of multiple myeloma.
It has been hypothesized that the association between excess body weight and multiple myeloma could be due to reduced expression of adiponectin; circulating levels of this anti-inflammatory hormone are typically lower in obese individuals compared to those with normal body weight. In support of this hypothesis, Dr. Hofmann and colleagues observed inverse associations with multiple myeloma for circulating adiponectin levels in a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Subsequently, they confirmed these results in a larger pooled investigation including six additional cohorts in the NCI Cohort Consortium. In another effort, they observed lower levels of adiponectin in patients with smoldering or active multiple myeloma compared to those with MGUS, suggesting that reduced expression of adiponectin may be associated with myeloma progression.
“Our results provide the strongest epidemiologic evidence to date that adiponectin may be associated with risk of developing multiple myeloma,” Dr. Hofmann said. “These findings may have implications for the clinical management of overweight and obese individuals, in particular for those with the precursor MGUS.”
He notes that in the recent Cohort Consortium analysis, adiponectin levels were lower among African Americans compared to those of European ancestry, after controlling for body mass index and other factors. Dr. Hofmann plans to expand on these intriguing findings with additional studies in cohorts with a greater proportion of African American participants. “This will facilitate future analyses stratified by race and will allow us to investigate differences in adiponectin levels and observed racial disparities in multiple myeloma.”
Severe immune dysregulation has also been reported as a risk factor for multiple myeloma. For example, risk is substantially elevated among solid organ transplant recipients receiving immunosuppressive medications and among HIV/AIDS patients. Researchers suspect that subclinical immune changes or disturbances may be associated with myeloma risk in the general population.
Despite strong experimental and clinical evidence that certain immunologic biomarkers are involved in multiple myeloma pathogenesis, few prospective studies to date have investigated them. Within PLCO, Dr. Hofmann is analyzing circulating immunologic markers among MGUS and multiple myeloma cases and MGUS-free controls; he presented preliminary findings at the 2018 AACR Annual Meeting.
“Our primary aim in this study is to identify circulating chemokines and angiogenic cytokines associated with future risk of multiple myeloma,” he said. “Beyond that, we want to get a better understanding of how and when these markers influence myeloma development, and whether they are involved in earlier or later stages of the disease process. We’re also evaluating whether these markers can help predict the likelihood of progression from MGUS to multiple myeloma.”
A distinctive feature of this effort is that investigators are studying subjects with MGUS status characterized at baseline, including those with MGUS who did or did not subsequently develop multiple myeloma. This work was made possible due to an ongoing collaboration with Dr. Landgren to identify MGUS in a large sample of PLCO participants and evaluate characteristics associated with progression.
“There’s a great deal of interest in improving our ability to identify MGUS patients at high risk of progression to myeloma,” Dr. Hofmann said. “I feel lucky to have the opportunity to do the molecular studies on multiple myeloma, and our studies on biomarkers related to progression. It’s a fascinating area, and there may be translational implications in terms of how MGUS patients are managed, and potential opportunities for secondary prevention.”
Hofmann JN, et al. The Biomarkers of Exposure and Effect in Agriculture (BEEA) Study: Rationale, design, methods, and participant characteristics. J Toxicol Environ Health A. 2015;78:1338-1347.
Landgren O, et al. Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study. Blood. 2009;113:6386-6391.
Alavanja MC, et al. Non-Hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study. PLoS One. 2014;9:e109332.
Lerro CC, et al. Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators. Occup Environ Med. 2018;75:79-89.
Hofmann JN, et al. Industrial hog farming is associated with altered circulating immunological markers. Occup Environ Med. 2018;75:212-217.
Hofmann JN, et al. A prospective study of circulating adipokine levels and risk of multiple myeloma. Blood. 2012; 120: 4418-4420.
Hofmann JN, et al. Low levels of circulating adiponectin are association with multiple myeloma risk in overweight and obese individuals. Cancer Res 2016;76:1935-1941.