In a first-of-its-kind retrospective study, Maaike van Gerwen, MD, PhD, Assistant Professor, Otolaryngology-Head and Neck Surgery, is exploring whether past exposure to Agent Orange—a highly destructive defoliant widely used during the Vietnam War—is associated with more aggressive thyroid cancer features, including lower survival, more aggressive genetic changes, and higher rates of metastasis and cancer recurrence.
Used as a tactical herbicide to control agricultural crop production in Vietnam, Agent Orange was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an endocrine-disrupting chemical with a biological half-life of up to 10 years that has been classified as a human carcinogen. While assessing the role of environmental exposures in the rising incidence of thyroid cancer has been challenging, U.S. military personnel who were exposed to Agent Orange may be able to provide insights into this troubling phenomenon.
“Multiple studies have shown that veterans of the Vietnam War who were exposed to TCDD have a higher incidence of thyroid cancer, but no study has explored whether exposure to TCDD is associated with more aggressive cancer features,” explains Dr. van Gerwen, faculty member within the Institute for Translational Epidemiology at Mount Sinai.
Examining DNA Methylation in Thyroid Cancer Patients
Dr. van Gerwen has partnered with the James J. Peters VA Medical Center in the Bronx to investigate the impact of this exposure, which provides her with access to a large population of Vietnam War veterans who have thyroid cancer.
To examine this retrospectively, Dr. van Gerwen will begin by analysing a nationwide dataset of VA patients with thyroid cancer to assess aggressiveness based on exposure status. Following this, she will source thyroid cancer pathology samples from 30 exposed patients who have undergone thyroidectomy surgery. Samples will then be matched based on sex and age with samples from 30 nonexposed patients. Using these samples, Dr. van Gerwen will look for signs of mutations and DNA methylation changes that have been linked with more aggressive cancer and assess whether they are more prevalent among the exposed cohort.
“DNA methylation changes have been described in all forms of cancer, including thyroid cancer,” Dr. van Gerwen says. “Concomitantly, DNA methylation can be modified by environmental exposures, and some "in vitro" and animal studies have shown the effects of TCDD exposure on DNA methylation. However, the relationship between TCDD exposure-linked DNA methylation and thyroid cancer aggressiveness has not been studied to date. Our hypothesis is that this exposure is associated with an aberrant methylation profile, in particular among tumor suppressor genes.”
Understanding the Effect of Endocrine Disrupting Chemicals on the Thyroid
The study, which is in its early stages, has the potential to impact management protocols for thyroid cancer patients who were exposed to Agent Orange or TCDD.
“If we discover that exposure is linked to more aggressive cancer, we can recommend that patients who have been exposed be followed closely or receive more aggressive treatment upon diagnosis,” says Dr. van Gerwen. “For example, we could adopt treatment guidelines that recommend complete removal of the thyroid gland among patients with small, low-risk cancers based on their exposure status.”
Results will also open the door for further research to evaluate the risk of developing aggressive thyroid cancer upon exposure to other endocrine disrupting chemicals, such as flame retardants used by active military personnel or per- and polyfluorinated alkyl substances—“forever chemicals ”—among the general population.
“Further exploration would put us on the path to unravel which environmental exposures are potentially associated with a higher risk of developing thyroid cancer,” she says. “The ability to identify these exposures and regulate them is the Holy Grail of our research. It is also possible that we could identify biomarkers associated with these exposures, which would bring us into the realm of personalized medicine.”
Maaike van Gerwen, MD, PhD
Assistant Professor Otolaryngology-Head and Neck Surgery