Mutational analysis using next generation sequencing in pediatric thyroid cancer reveals BRAF and fusion oncogenes are common

• Published in: International journal of pediatric otorhinolaryngology Vol. 157; p. 111121
• Main Authors: Newfield, Ron S., Jiang, Wen, Sugganth, Daniel X., Hantash, Feras M., Lee, Euyhyun, Newbury, Robert O.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.06.2022
• Subjects: Adolescent; BRAF; DNA Mutational Analysis; Female; Fusion-oncogenes; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation; NGS; Oncogene Proteins, Fusion - genetics; Oncogenes; Pediatric; PPAR gamma - genetics; Proto-Oncogene Proteins B-raf - genetics; Receptor Protein-Tyrosine Kinases - genetics; RET-PTC; Retrospective Studies; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Well-differentiated thyroid carcinoma; Well-differentiated thyroid carcinoma; RET-PTC; BRAF; Fusion-oncogenes; NGS; Pediatric
• ISSN: 0165-5876; 1872-8464; 1872-8464
• DOI: 10.1016/j.ijporl.2022.111121

We previously described mutation rates of BRAFV600E, RAS, RET-PTC and PAX8-PPARγ in pediatric subjects with well-differentiated thyroid cancer (WDTC). We expanded the cohort adding next-generation sequencing (NGS) and assessed genotype-phenotype correlations. Single-center retrospective cohort examining thyroidectomy tissue blocks from consecutive pediatric WDTC patients between 2001 and 2015. Tissues were analyzed at Quest Diagnostics for BRAF, RAS mutations, RET-PTC and PAX8-PPARγ, and additional fusions, using standalone and NGS tests. WDTC included papillary (PTC), follicular (FTC) and follicular-variant PTC (FVPTC). We genotyped 46 samples (36 females). Mean age at diagnosis was 14.7 years and the cohort comprised of mostly Hispanic (60.9%) and Caucasian (26.1%) patients. Mean follow-up was 3.5 years. Genetic alterations (GA) were noted in 69.6%, with BRAFV600E (n = 11), and RET-PTC (n = 8) detected only in PTC. GA were detected in 2/7 FTC (1 PAX8-PPARγ, 1 NRAS) and 6/10 FVPTC (3 PAX8-PPARγ, 1 STRN-ALK, 1 BRAFK601E, 1 NRAS). Patients with BRAFV600E were predominantly Hispanic (81.8%) and >15 years (81.8%), whereas 87.5% RET-PTC and 50% other-fusions occurred in patients ≤15 years (p = 0.044). Of the 29 PTC patients, 82.8% had GA: BRAFV600E (37.9%), RET-PTC (27.6%), 17.2% other fusion-oncogenes (2 -ALK, 3 -NTRK). Non-RET fusions had the highest vascular invasion (100%, p = 0.042 vs RET-PTC) and frequent lymphatic invasion (80%). GA were most common in PTC with cervical metastasis. BRAFV600E was the most common single mutation, especially in older and Hispanic adolescents. All fusions combined are more common than BRAFV600E. NGS reveals a genetic basis in most pediatric WDTC, which may have implications for the role of molecular testing and systemic therapy. •Fusions are common in pediatric PTC.•Fusions with more invasion ≠ more metastases.•BRAFV600E was the most common single-gene mutation.•About half of PTC patients had Hashimoto’s thyroiditis.