Compared to adult thyroid cancers, which are largely driven by BRAF and RAS mutations, pediatric nodules are dominated by gene fusions and DICER1 variants, according to a new study in JAMA Oncology.
Led by investigators at Vanderbilt University Medical Center, the study also demonstrated that a next-generation sequencing (NGS) test can discriminate benign from malignant nodules in children, which may reduce the need for diagnostic surgery.
“We are putting a lot of kids through unnecessary surgery because we aren’t able to tell if the nodule is malignant or benign,” said Vivian Weiss, M.D., senior author on the study and an assistant professor in the Department of Pathology, Microbiology and Immunology at Vanderbilt.
“The point of our study was to understand whether there are mutations or genetic alterations that we can identify in children that would give us a better chance of predicting malignancy prior to surgery.”
The study findings may also have implications for treatment, as some of the alterations associated with malignancy are targetable fusions, including NTRK and RET.
Pediatric Guidelines
When diagnosing thyroid cancer, fine-needle aspiration is the most widely used method. However, biopsies are frequently inconclusive, with indeterminate results occurring in 20 to 30 percent of cases, Weiss said.
When indeterminate biopsies occur in adults, patients undergo a follow-up biopsy and often molecular testing. But because thyroid nodules in children carry an increased risk of malignancy, current guidelines for pediatric patients from the American Thyroid Association recommend immediate diagnostic surgery after an indeterminate biopsy.
“The point of our study was to understand whether there are mutations or genetic alterations that we can identify in children that would give us a better chance of predicting malignancy prior to surgery.”
“Quite a large percentage of those come back not being cancer, which is a great thing, but then the child has lost part or all of their thyroid in the process,” Weiss said.
With funding from the V Foundation for Cancer Research as well as the Children’s Cancer Research Fund, Weiss has been working to improve diagnosis by addressing this gap in knowledge of molecular drivers of pediatric thyroid cancer.
Fusions Predominate
The new study is a retrospective case series of every pediatric thyroid surgery performed at Vanderbilt from 2003 to 2019. Of the 95 pediatric patients studied, 53 percent had malignant nodules, according to final pathology results.
Using comprehensive sequencing of archived surgical tissue, Weiss and colleagues found that 58 percent of malignant nodules harbored a gene fusion, with most fusions (90 percent) involving RET and NRTK1/3.
In contrast, pathogenic variants associated with adult thyroid cancer, including BRAF, RAS, TP53 and TERT, are much less common or even absent in pediatric tumors.
“Despite having an aggressive enough tumor that a child had a lethal disease, that child did not have a TP53 or TERT promoter mutation,” Weiss said. “In an adult, they would most certainly have one of those two.
“The study findings are very interesting to us because it means that the genetic drivers in children are quite different, even if it results in the same type of cancer or same morphology.”
Benign nodules were mostly associated with TSHR (42 percent) and DICER1 (13 percent) variants, however DICER1 variants were also identified in 8 percent of malignant nodules. Weiss explains that this aligns with adult RAS alterations, which are also found in both benign and malignant nodules. She suspects a DICER1 mutation may be “one step on the road to malignancy.”
“DICER1 alone doesn’t look like it correlates with malignancy, but DICER1 plus a secondary alteration, commonly a copy number alteration, may be more indicative of a malignant nodule,” Weiss said.
Assay Performance Promising
The authors also used archived patient samples to evaluate the diagnostic accuracy of the ThryoSeq Genomic Classifier NGS test, reporting 96 percent sensitivity and 78 percent specificity. The test resulted in false negatives for 4 percent of cases, all of which were low risk, differentiated cancers, and false positives for 22 percent of cases, many of which harbored a DICER1 variant.
Weiss hopes the test will soon become an option for pediatric patients but stresses more research is needed.
“The study findings are very interesting to us because it means that the genetic drivers in children are quite different, even if it results in the same type of cancer or same morphology.”
“We will have to see if the assay has the same sensitivity and specificity if it is applied to other areas and populations in real time.”
Looking ahead, she already has her sights set on clarifying the role of DICER1 in tumorigenesis.
“We’re going to focus quite a bit of our effort on understanding DICER1 in pediatric thyroid cancer pathogenesis using exciting tools in the lab, including 3D cell culture models,” she said.
