Supplementary Material for: Clinical Impact of Genetic Alterations in Pediatric Papillary Thyroid Carcinoma: A Next-Generation Sequencing Study from Argentina

Background: In children, papillary thyroid cancer (PTC) is generally sporadic and may, less frequently, be part of an undiagnosed hereditary tumor predisposition syndrome. Somatic molecular testing is useful to understand tumor etiology and behavior, predict prognosis, and possibly guide development of novel treatment strategies. The aims of our study were to analyze the findings of a next-generation sequencing (NGS) panel in a cohort of pediatric PTC from Argentina according to age at presentation, recurrence risk, and response to treatment.
Material and Methods: A retrospective descriptive study was conducted of 63 consecutive pediatric patients with PTC seen at a single center in whom a DNA-based NGS panel was performed. The patients were classified according to the ATA-2015 recurrence risk stratification into a low (n:10), an intermediate (n:13), and a high-risk group (n:40). All patients were treated with total thyroidectomy and radioiodine. At the last follow-up, patients were classified as excellent response (ER) or having persistent disease (PD).
Results: In 70% (44/63) of the samples, a pathogenic somatic variant was detected, the most frequent alterations were RET fusions (20%). Fusions were more frequent in younger patients (median age 11.45 vs 13.7 years; p:0.048), in diffuse sclerosing subtype histology (p:0.01) and in high-recurrence risk group (p<0.014). The risk of PD was higher in patients in the high-risk group (odds ratio, 9.2).
When evaluating treatment response based on molecular findings, we found that among the 25 patients who achieved ER, 12 (48%) had fusions and 13 (52%) had point variants, with no statistically significant difference. However, among the 19 patients with PD, 12 (64%) had fusions and 7 (36%) had point variants, a difference that was statistically significant (p < 0.01).
In 5/63 (8%), pathological germline mutations were observed in genes associated with hereditary tumor predisposition syndromes (HTPS): DICER1 (n:2), PTEN (n:1), and MSH6 (n:2).
Conclusions: Interestingly, in our PTC cohort the NGS panel was highly specific to detect molecular alterations. Fusions were more frequent at a younger age and in the ATA-2015 high-recurrence-risk group; however, it was not a determining factor to predict PTC outcome. Finally, detection of pathological germline mutations in genes involved in HTPS was useful for genetic counselling.