Mutational analysis of radiation-induced subsequent thyroid cancers in pediatric patients.

Abstract

e22531 Background: The genetic landscape of radiation induced pediatric thyroid cancers is unclear. Radiation (RT) induced thyroid cancers frequently demonstrate tumorigenesis driven by fusion oncogenes. However, data is limited to children exposed to radioactive contamination after the Chernobyl nuclear accident. Little is known about the genetic landscape of subsequent pediatric thyroid cancers after RT exposure for the treatment of a primary malignancy or conditioning regimens prior to bone marrow transplantation (BMT). The objective of this study was to assess the prevalence of different mutations in a small cohort of pediatric patients who developed a subsequent thyroid cancer after RT exposure for the treatment of a primary disease. Methods: This is a single-center retrospective study. Thyroid tissue blocks from 10 pediatric patients who underwent thyroidectomy between 2010 and 2019 for subsequent thyroid cancers after RT for treatment of a primary malignancy or BMT were analyzed for genetic alterations using targeted next-generation sequencing for alterations in 112 genes linked to thyroid cancer. Thyroid cancers included 7 papillary (PTC) and 3 follicular thyroid carcinomas (FTC). Results: Ten samples (6 females) were genotyped. The mean age at thyroid cancer diagnosis was 15.7 years (range 11–22 years) at a mean of 10.3 years (range 6 – 19 years) after RT exposure. The mean RT dose was 2618 cGy (range 400 – 10,080 cGy) delivered to the head, neck, and/or chest. Mutations were noted in 6/10 (60%) of patients. Mutations were detected in 6/7 (85.7%) of PTC cases: EMLA/NTRK in 2 cases, STRN/ALK in 2 cases, RET in 1 case, and CCDC30/ROS in 1 case. A DICER.1 c.5438A > C p.E1813A was also identified in a patient with an EMLA/NTRK fusion. Of 3 FTC patients, (2/3) 67% had copy number alterations, but no mutations were observed. BRAFV600E mutations were not present in any tissues analyzed. Conclusions: An exceedinlgy rare ROS fusion was identified. Multiple RT induced thyroid lesions were positive for classic therapeutic targets including NTRK3, ALK, ROS1, and RET fusions, demonstrating a potential role for tyrosine kinase inhibitor therapy for refractory, recurrent or metastatic disease. All cases were negative for mutant BRAFV600E consistent with the pathogenesis of RT induced thyroid cancers primarily activated by fusions rather than point mutations. Larger, pediatric cohorts with RT induced thyroid cancers followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.