title: Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.
abstract: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality.
  
  
  
  Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC).
  
  
  
  GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition toBRAFV600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involvingRET,NTRK1,NTRK3, andALKwere detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harboredRETalterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations inRETexperienced clinical benefit from vandetanib treatment.
  
  
  
  CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy.The Oncologist2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA pvandenborre@foundationmedicine.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanden Borre
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Anderson
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Heilmann
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Johnson
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Waguespack
authors.affiliation: Chao Comprehensive Cancer Center, Irvine, California, USA.
authors.forename: Sai-Hong Ignatius
authors.initials: SI
authors.lastname: Ou
authors.affiliation: University of Texas Southwestern, Dallas, Texas, USA.
authors.forename: Saad
authors.initials: S
authors.lastname: Khan
authors.affiliation: Stephenson Cancer Center, University of Oklahoma, Oklahoma City, Oklahoma, USA.
authors.forename: Kar-Ming
authors.initials: KM
authors.lastname: Fung
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Erlich
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.|Albany Medical Center, Albany, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
mesh_terms: D000293:Adolescent; D000328:Adult; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000302:isolation & purification; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D015514:Oncogene Proteins, Fusion; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Comprehensive genomic profiling; Fusion; Genomics; Molecular targeted therapy; Oncogene proteins; Thyroid carcinoma; Vandetanib