Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions

Abstract

Background: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality.

Methods: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC).

Results: GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment.

Conclusion: CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.

Keywords: Comprehensive genomic profiling; Fusion; Genomics; Molecular targeted therapy; Oncogene proteins; Thyroid carcinoma; Vandetanib.

Figure 1.

Alteration classes detected by comprehensive genomic profiling of patients with thyroid carcinoma. (A): A total of 1,478 GAs were detected in 512 patients with thyroid carcinoma. (B): Percentage of alteration classes detected among 753 GAs in patients with PTC, 583 GAs in patients with ATC, and 142 GAs in patients with MTC. (C): Percentage of alteration classes detected among 54 GAs in patients younger than 40 years of age at the time of biopsy with PTC, 8 GAs in patients younger than 40 years of age at the time of biopsy with ATC, and 19 GAs in patients younger than 40 years of age at the time of biopsy with MTC. SNVs (blue) are more common in younger patients. Abbreviations: ATC, anaplastic thyroid carcinoma; AYA, adolescent and young adult; GA, genomic alterations; MTC, medullary thyroid carcinoma; PAYA, pediatric, adolescent, and young adult; PTC, papillary thyroid carcinoma; SNV, single nucleotide variants.

Figure 2.

Tile plot of genomic alterations identified in patients under the age of 40 years at the time of comprehensive genomic profiling. A total of 58 pediatric, adolescent, and young adult patients, including 41 with PTC, 3 with ATC, and 15 with MTC. Additional details shown include age at time of sample collection, gender, metastatic disease (black box), and specimen site. Abbreviations: ATC, anaplastic thyroid carcinoma; F, female; LN, lymph node; M, male; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma.

Figure 3.

Distribution of oncogenic fusions detected by CGP in papillary and anaplastic thyroid carcinomas. Distribution of (A) 303 patients with papillary thyroid carcinoma ranging from 7 to 96 years of age and (B) 132 patients with anaplastic thyroid carcinoma ranging from 25 to 86 years of age at the time of sample collection. Patients harboring oncogenic fusions are highlighted. Abbreviation: CGP, comprehensive genomic profiling.

Figure 4.

Schematic diagram of fusions detected in pediatric, adolescent, and young adult (PAYA) patients with papillary thyroid carcinoma (PTC) or anaplastic thyroid carcinoma (ATC) and RET mutations in PAYA patients with medullary thyroid carcinoma (MTC). (A): Oncogenic RET (11/41), ALK (3/41) and NTRK3 (1/41) kinase fusions identified by comprehensive genomic profiling (CGP) in PAYA patients with PTC. NCOA4‐RET fusions were detected in 7 cases, whereas the other fusions were detected in single cases. Breakpoints were detected in both intron 7 and exon 8 of NCOA4. (B): A TPM3‐NTRK1 fusion was identified by CGP in 1 of 3 AYA patients with ATC. (C): RET missense mutations and indels were identified by CGP in 13 of 14 PAYA patients with MTC. Ten cases harbored RET M918T, whereas indels were detected in exons 6 or 11 in 3 cases.

Figure 5.

Clinical response to vandetanib in a 16‐year‐old with both long‐standing Hirschsprung disease and metastatic medullary thyroid carcinoma (mediastinum, lungs, liver, bone) whose tumor harbors an indel within RET exon 6 (D378_G385>E). Abbreviation: CEA, carcinoembryonic antigen.