Burkitt's lymphoma cells, is a cancer of the lymphatic system
Burkitt's lymphoma cells, a cancer of the lymphatic system, monoclonal B-cell tumor, 3D illustration

Three sets of mutations are associated with aggressive pediatric thyroid cancers and those that matter most in children differ significantly from what is seen in adults, according to a new study. The three categories are RAS-mutant, BRAF-mutant, and RET/NTRK fusions. This work supports the use of genetic analysis of these cancers.

The findings, from researchers at Children’s Hospital of Philadelphia (CHOP), were published in the Journal of Clinical Oncology.

“Our data support that genetic subtyping of pediatric DTC [differential thyroid cancer] more accurately reflects clinical behavior than sole reliance on pathologic classification,” the authors write.

They found children with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at one year than patients within RAS- or BRAF-mut subgroups. This contrast findings in adults, for whom BRAF mutations, not fusion oncogenes, are associated with more invasive disease that is less responsive to therapy.

“Considering the high prevalence of RET/NTRK fusions in pediatric differentiated thyroid cancer, and their association with more metastatic behavior, it will be crucial to generate the transcriptional signatures of RET/NTRK and BRAF-mutant subgroups in the pediatric population to understand the differential impact of these alterations on signaling pathways, differentiation, and clinical outcomes,” said first author Aime T. Franco, director of the Pediatric Thyroid Cancer Translational Research Laboratory at CHOP.

The results from the CHOP thyroid team are a pediatric-specific follow-on study to the 2014 Cancer Genome Atlas (TCGA) report that classified adult papillary thyroid cancer (PTC) into two molecular subtypes—RAS-like or BRAF-like—and concluded that molecular classification more accurately reflected tumor behavior, including disease severity and prognosis.

To determine whether the adult based TCGA classification predicted the similar clinical behavior and outcomes in pediatric patients with DTC, the CHOP researchers analyzed 131 pediatric thyroid tumors. Of those, 66 were collected and sequenced using the CHOP Division of Genomic Diagnostics platform between 2016 and 2019. The remaining 65 were collected between 1989 and 2012 and sequenced on a commercial platform (Asuragen).

In analyzing the sequenced samples, the researchers categorized mutated genes into three categories: RAS-mutant, BRAF-mutant, and RET/NTRK fusions. These categories were evaluated against numerous parameters, including patient demographics, thyroid pathology, and clinical characteristics.

They found that the three-tier classification system more accurately reflected the clinical behavior of DTC in pediatrics. Notably, the researchers found no distant metastasis in any patients with BRAF-mutant thyroid tumors, whereas 36% of patients with RET/NTRK fusions had distant metastasis. Persistent disease at one year was also more frequent in the subgroup harboring RET/NTRK fusions: 36% vs. 17% among those with a BRAF mutation.

“This study shows fusion oncogenes are more prevalent in pediatric thyroid cancer that is likely to spread to the lungs, whereas tumors with RAS-like and BRAF mutations are associated with low- and intermediate risk, respectively,” said Andrew J. Bauer, Director of the Pediatric Thyroid Center at CHOP and senior author of the study.

He added that, “This provides an opportunity for increased collaboration among surgeons, endocrinologists, and oncologists to stratify the treatment of tumors, approaching RAS-like mutations with less extensive surgery, while also exploring the new treatment protocols using FDA-approved oncogene specific inhibitors to optimize the treatment of patients with lung metastasis.”

Patient age was an important factor. In line with prior studies, the researchers found that RET/NTRK fusions are more common in patients under the age of 10. Of the samples in their analysis, 91% of those in patients under the age of 10 harbored fusion events. The prevalence gradually decreased in pediatric patients older than 10 years (27%) and into adulthood (9%). By contrast, only one BRAF mutation (9%) was found among patients under the age of 10, compared with 25 pediatric patients aged 10 years or older (20%) and 58% of adults with PTC.

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