Paper Details

ABSTRACT

Background:

Myeloproliferative neoplasms (MPN) are hematologic malignancies that are characterized largely by overproduction of red blood cells (RBCs), platelets, and white blood cells (WBCs), likely related to cell-intrinsic clonal events. Globally, MPNs comprise 0.5% of all new cancer cases in the U.S. There are genetic risk factors common to multiple types of MPN, such as mutations in JAK2, MPL, and CALR as well as BCR-ABL fusion mutations. Environmentally, exposure to ionizing radiation is a distinct risk factor. U.S. Vietnam Veterans were found to have a higher risk of MPN compared to their counterparts who served in the Korean War. One cause could be due to exposure to Agent Orange (AO), which was used as an herbicide and defoliant. AO was contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a known carcinogen associated with disruption of apoptosis, generation of reactive oxygen species, and inflammation. Thus, we sought to further characterize the relationship between AO exposure and development of MPN using the VA Million Veteran Program (MVP).

Methods:

Using the VA MVP cohort, which enrolled Veterans who provided blood samples and surveys to provided genetic, lifestyle, and military history data, we conducted a matched case-control study that was restricted to Vietnam Veterans. We queried the VA Central Cancer Registry for incident cases of MPN (polycythemia vera, essential thrombocythemia, and myelofibrosis), myelodysplastic syndrome (MDS)/MPN overlap syndromes (including chronic myelomonocytic leukemia), and chronic myeloid leukemia (CML). Controls were matched 4:1 based on birth year +/- 5 years and sex, restricting controls with follow-up time to date of death or last follow up to equal at least the median time to diagnosis of cases. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with multivariable logistic regression models, adjusted for sex, race and ethnicity, age at MVP enrollment, and smoking history.

Results:

Among 306,265 Vietnam Veterans analyzed, 168 cases of MPN were identified compared to the 730 controls, with 57% of both groups reporting AO exposure. The median age of both groups was 67 years (interquartile range [IQR] 6 years). Both the case and control groups were predominantly male (98%), White (77% vs 80%), ever smokers (78% vs 73%), and had enlisted in the Army (43% vs 51%). AO exposure was not associated with MPN (OR 1.02, 95% CI 0.72-1.44).

There were 104 cases of MDS/MPN overlap and 417 controls identified with complete AO exposure data. The median age at MVP enrollment of cases and controls was 67 years (IQR 65-70 years) vs 68 years (65-71 years), respectively. The cases and controls were mostly male (98%), White (74% vs 78%), ever smokers (76% vs 71%), and had enlisted in the Army (46% vs 47%). Almost half of cases (46%) and controls (48%) reported AO exposure. There was no association between AO exposure and the risk of the development of MDS/MPN (OR 0.89, 95% CI 0.57-1.41).

Of those diagnosed with CML, there were 99 cases with 383 controls. Over half of cases and controls had AO exposure (59% vs 57%, respectively). The median age of cases and control was 67 year (IQR 5 years); most were male (99% in both), White (81% vs 80%), and about half had enlisted in the Army 54% vs 45%. More cases were ever smokers (86% vs 69%). CML was not associated with AO exposure (OR 1.06, 95% CI 0.66-1.67).

Conclusion:

In this large case-control study, AO exposure was not associated with increased risk of developing MPN, MDS/MPN, or CML using the MVP cohort. These findings support that MPN, MDS/MPN, and CML are likely driven by oncogenic mechanisms distinct from dioxin-induced inflammation, and genotoxic damage.