Clinical relevance of findings of the NGS panel for the pediatric patient with papillary thyroid carcinoma

Noelia Dujovne; Natalia Gazek; Elisa Vaiani; Pablo Ramirez; Garrido Natalia Perez; Roxana Marino; Marti Jessica Lopez; Victor Ayarzabal; Marta Ciaccio; Alicia Belgorosky; Viviana Herzovich

Background: In children, papillary thyroid cancer (PTC) is generally sporadic and may, less frequently, be part of an undiagnosed hereditary tumor predisposition syndrome (HTPS). Somatic molecular testing is useful to understand tumor etiology and behavior, predict prognosis, and possibly guide development of novel treatment strategies. RET/PTC fusions were found to be associated with an increased risk of invasive disease. The aims of our study were to analyze the findings of a next-generation sequencing (NGS) panel in a cohort of pediatric PTC according to age at presentation, recurrence risk, and response to treatment and to detect patients with HTPS.

Material and Methods: A retrospective descriptive study was conducted of 63 pediatric patients with PTC seen at a single center in whom a DNA-based NGS panel was performed targeting 54 thyroid cancer-related genes. Pathological molecular alterations were validated by DNA sanger sequencing in tissue and peripheral blood DNA samples to provide evidence of germline mutations. Recurrence risk was classified according to ATA-2015 as low (G1; n: 10), intermediate (G2; n: 13), and high (G3; n: 40). All patients were treated with total thyroidectomy and radioiodine. At the last follow-up, patients were classified as disease free (DF) or having persistent disease (PD). Mean (SD) follow-up was 4.48 (2.11) years.

Results: In 70% (44/63)of the samples, a pathogenic variant or gene fusion was detected: G1: 80%, G2: 54%, and G3: 63%. The most frequent alterations were RET-fusion (20%), ALK-fusions (14%), and BRAF (12 %). In 6/63 (9.5 %), pathological germline mutations were observed in genes associated with HTPS: DICER1 (n: 3), PTEN (n: 1), Lynch syndrome/ MSH6 (n: 2). Chronological age was significantly lower in patients with gene fusions (median age 11.45 vs 13.7 years; p: 0.048). Mutations most frequently associated with PD were RET/NCOA4 (RET/PTC3) (3/4;75%), STRN/ALK (4/8;50%), BRAF (4/8;50%), RET-CCDC6 (RET-PTC1) (3/9;33%), MSH6 (1/3;33%), and DICER1 (1/5;20%). Overall, 43% of those with a positive NGS panel had PD versus 52% of those with a negative. Fusions were more often found in G3 (21/29; 72%), but DF and PD were not related to fusions found.

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 G3; however, it was not a determining factor to predict PTC outcome. Finally, detection of pathological germline mutations in genes involved in HTPS is a useful tool for genetic counselling.

ESPE Abstracts

T5