Application of genomics to identify therapeutic targets in recurrent pediatric papillary thyroid carcinoma

Abstract

Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding. Identification of oncogenic drivers in recurrent pediatric PTC may facilitate targeted therapy while avoiding repeated RAI.

Keywords: metastatic angiosarcoma; papillary thyroid carcinoma.

Figure 1.

TPM3-NTRK1 and RET-CCDC6 oncogenic fusions with exon numbers and protein domains. (A) TPM3-NTRK1 fusion. Chr 1, Chromosome 1; B1, breakpoint that falls into TPM3; B2, breakpoint that falls into NTRK1; T1, transcript of TPM3 (ENST00000368530); T2, transcript of NTRK1 (ENST00000368196). The numbers on T1 and T2 indicate exons. Pfam domains and accession IDs are labeled beneath the transcripts. (B) RET-CCDC6 fusion. Chr 10, Chromosome 10; B1, breakpoint that falls into RET; B2, breakpoint that falls into CCDC6; T1, transcript of RET (ENST00000355710); T2, transcript of CCDC6 (ENST00000263102).

Figure 2.

(A) High NTRK1 RNA expression in Patient 1 compared to 513 tumor samples from TCGA thyroid (THCA) cohort and 59 matched normal samples. The distributions of NTRK1 expression in the tumor and normal groups are shown as density curve. The gray line indicates NTRK1 expression in a normal thyroid sample from Illumina body map. (B) High RET RNA expression in Patient 2 compared to 513 tumor samples from TCGA thyroid (THCA) cohort and 59 matched normal samples. The distributions of RET expression in the tumor and normal groups are shown as density curve. The gray line indicates RET expression in a normal thyroid sample from Illumina body map.

Figure 3.

Pre- and posttherapy CT chest images for Case 1. (A) Axial CT chest image demonstrating a large (6-mm) pulmonary nodule (red arrow) prior to oral TRK inhibitor therapy initiation. At baseline, the patient had progressive innumerable, small pulmonary nodules demonstrated throughout the lungs bilaterally. (B) Coregistered axial CT image following four cycles of oral TRK inhibitor therapy demonstrating resolution of the prior pulmonary nodule (red circle) documented at baseline.