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Gregory J. Riely, MD, PhD


Age-Dependent Biologic Consequences of NTRK and RET Gene Fusions in Thyroid Cancer

By: Julia Fiederlein
Posted: Monday, May 16, 2022

An installment of the Understanding the Pathway series, which was published in the Journal of Clinical Oncology, provided a few possible explanations for the distinct age-dependent biologic consequences of NTRK and RET gene fusions in patients with thyroid cancer. To aid in discussing this clinical question, James A. Fagin, MD, of the Weill Cornell Medical College, New York, referenced a single-institution retrospective study describing novel genotype-phenotype correlations.

In brief, NTRK and RET gene fusions have been found to occur at a higher frequency in pediatric patients with papillary thyroid cancer compared with their adult counterparts. In the study conducted by Aime T. Franco, PhD, of the Children’s Hospital of Philadelphia, and colleagues, pediatric tumors driven by these gene fusions seemed to develop nodal and distant metastases more frequently than fusion-negative tumors and genotype-matched adult tumors, respectively.

“The study by Dr. Franco [and colleagues] points to fundamental gaps in our understanding of the…mechanisms responsible for the effects of age and sex on the manifestations of differentiated thyroid cancers,” Dr. Fagin commented. “The findings…are likely to be clinically consequential, particularly if clinical trials with RET and NTRK inhibitors prove to be beneficial for children with metastatic thyroid cancer, either as redifferentiation agents to enhance responses to radioiodine or as a standard systemic therapy for rapidly progressive disease.”

One possible explanation for the distinct age-dependent biologic consequences of NTRK and RET gene fusions is that pediatric patients harbor additional genetic alterations; however, according to Dr. Fagin, this is unlikely due to a lower frequency of simple somatic variants in younger patients. A second possibility is the signaling output of identical gene fusions may differ based on age. Third, these gene fusions may arise in thyrocytes that are at a different developmental stage or subject to distinct environmental cues.

Disclosure: For full disclosures of the study author, visit

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