title: Fusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children.
abstract: Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients.
  
  
  
  Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAFV600Eand NRASQ61) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data.
  
  
  
  Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAFV600Ein 3 (9%). No mutation was found in NRASQ61. BRAFV600Ewas associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05).
  
  
  
  The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.
authors.affiliation: 1 Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Maria Isabel C Vieira
authors.initials: MI
authors.lastname: Cordioli
authors.affiliation: 1 Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Lais
authors.initials: L
authors.lastname: Moraes
authors.affiliation: 1 Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: André U
authors.initials: AU
authors.lastname: Bastos
authors.affiliation: 1 Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Paloma
authors.initials: P
authors.lastname: Besson
authors.affiliation: 2 Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Maria Teresa de Seixas
authors.initials: MT
authors.lastname: Alves
authors.affiliation: 2 Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Rosana
authors.initials: R
authors.lastname: Delcelo
authors.affiliation: 3 Pediatric Division, Faculdade de Ciências Médicas, Irmandade da Santa Casa de Misericórdia de São Paulo , São Paulo, SP, Brazil .
authors.forename: Osmar
authors.initials: O
authors.lastname: Monte
authors.affiliation: 3 Pediatric Division, Faculdade de Ciências Médicas, Irmandade da Santa Casa de Misericórdia de São Paulo , São Paulo, SP, Brazil .
authors.forename: Carlos
authors.initials: C
authors.lastname: Longui
authors.affiliation: 4 Division of Endocrinology, Department of Medicine, Faculdade de Ciências Médicas, Irmandade da Santa Casa de Misericórdia de São Paulo , São Paulo, SP, Brazil .
authors.forename: Adriano Namo
authors.initials: AN
authors.lastname: Cury
authors.affiliation: 1 Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics and Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, SP, Brazil .
authors.forename: Janete M
authors.initials: JM
authors.lastname: Cerutti
mesh_terms: D000293:Adolescent; D002291:Carcinoma, Papillary / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D056918:Nuclear Receptor Coactivators / Q000235:genetics; D050596:Oncogene Fusion / Q000235:genetics*; D000072081:Patched-1 Receptor / Q000235:genetics; D000072082:Patched-2 Receptor / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D056918:Nuclear Receptor Coactivators; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D017853:Phosphotransferases (Alcohol Group Acceptor); D048493:Proto-Oncogene Proteins B-raf; D050783:Proto-Oncogene Proteins c-ets; D051096:Proto-Oncogene Proteins c-ret; D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C111382:NCOA4 protein, human; C000606236:PTCH1 protein, human; C000606238:PTCH2 protein, human; C492429:AGK protein, human; C099282:RET protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human
keywords: AGK-BRAF; BRAF; ETV6-NTRK3; RET/PTC; pediatric thyroid carcinomas