Introduction:
Papillary thyroid carcinoma (PTC) accounts for 90% of thyroid malignancies in children and is especially prevalent among females aged 15-19 years, in whom it is the second most common malignancy1. Pediatric PTC patients are more likely to present with metastatic disease and have a higher likelihood of relapse as compared to their adult counterparts2,3. Standard therapy for pediatric PTC most often involves total thyroidectomy (+/- lymph node dissection) as well as radioactive iodine therapy (RAI) for selected cases. While the prognosis for patients who have undergone standard therapy is excellent, with a 15-year overall survival of 95% 4, there is significant morbidity secondary to surgical procedures and radiation exposure 5.
Much of our knowledge regarding the genomic landscape of PTC can be attributed to The Cancer Genome Atlas (TCGA) project, which comprehensively analyzed 496 tumors and matched germline samples. This study revealed that adult PTC is characterized by a relatively quiet genome with mutually exclusive driving somatic genetic alterations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways6. However, as only 5 of the samples analyzed were from patients less than 19 years of age, the extent to which these findings are applicable to childhood PTC was not known. Instead, our understanding of the genomic landscape of pediatric PTC and corresponding clinical correlations relies on data generated from smaller pediatric cohorts analyzed by varying molecular methods.
These pediatric studies suggest that point mutations regularly found in adult PTC, such as BRAF V600E, are identified less frequently in children, whereas gene fusions are more common1,7-9. Other studies note a correlation between the prevalence of oncogenic alterations and patient age, attributed to the more frequent presence of the BRAF V600E mutation in older patients10. Unlike in adults, the presence of a BRAF V600E mutation in pediatric patients does not necessarily correlate with a more aggressive phenotype11,12. Rather, recent papers have suggested that pediatric thyroid tumors driven by fusion genes, such as RET/PTC1 and NTRK3-ETV6 , may be correlated with more invasive disease13,14.
Analysis from the Chernobyl nuclear accident helped delineate some of the differences between radiation-induced and sporadic pediatric PTCs. Ricarte-Filho et al found that radiation-induced pediatric PTCs have an increased prevalence of fusion oncogenes compared to sporadic tumors, with the vast majority of these fusions targeting genes (RET , NTRK1 and NTRK3 , BRAF ) that activate the MAPK signaling pathway15. RETrearrangements are also common in sporadic pediatric PTC, however, with rates ranging from 17% to 58%13-16. Additionally, sporadic pediatric PTCs have been observed to have a larger number of point mutations compared to radiation-induced PTCs, particularly inBRAF and RAS genes15,17.
While each of these studies has provided additional insight into the nature of pediatric PTC, the molecular methods utilized have varied significantly and largely relied on targeted analysis of known PTC genes. We sought to perform more extensive DNA and RNA-based sequencing of a cohort of clinically-annotated tumors, with a specific focus on patients with metastatic, relapsed or refractory disease, in order to identify genetic alterations that might inform improved diagnostic and therapeutic approaches for these patients.