title: Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.
abstract: The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Picarsic
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Buryk
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ozolek
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Monaco
authors.affiliation: 4 Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Simons
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Selma F
authors.initials: SF
authors.lastname: Witchel
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Nursen
authors.initials: N
authors.lastname: Gurtunca
authors.affiliation: 3 Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Joyce
authors.affiliation: 2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D000293:Adolescent; D000367:Age Factors; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D002648:Child; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics*; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm
keywords: ETV6/NTRK3; gene fusions; molecular diagnostics; molecular pathology; pediatric; thyroid neoplasms