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Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma
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  • Samara Potter,
  • Jacquelyn Reuther,
  • Raghu Chandramohan,
  • Ilavarasi Gandhi,
  • Faith Hollingsworth,
  • Hadi Sayeed,
  • Horatiu Voicu,
  • Nipun Kakkar,
  • Koel Sen Baksi,
  • Stephen Sarabia,
  • Monica Lopez,
  • Daniel Chelius,
  • Ioanna Athanassaki,
  • Priya Mahajan,
  • Rajkumar Venkatramani,
  • Norma Quintanilla,
  • Dolores Lopez-Terrada,
  • Angshumoy Roy,
  • Donald Parsons
Samara Potter
Texas Children's Cancer Center

Corresponding Author:[email protected]

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Jacquelyn Reuther
Baylor College of Medicine
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Raghu Chandramohan
Baylor College of Medicine
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Ilavarasi Gandhi
Baylor College of Medicine
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Faith Hollingsworth
Baylor College of Medicine
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Hadi Sayeed
Texas Children's Hospital
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Horatiu Voicu
Texas Children's Hospital
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Nipun Kakkar
Texas Children's Cancer Center
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Koel Sen Baksi
Texas Children's Cancer Center
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Stephen Sarabia
Baylor College of Medicine
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Monica Lopez
Texas Children's Hospital
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Daniel Chelius
Texas Children's Hospital
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Ioanna Athanassaki
Baylor College of Medicine
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Priya Mahajan
Texas Children's Cancer Center
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Rajkumar Venkatramani
Texas Children's Hospital
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Norma Quintanilla
Texas Children's Hospital
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Dolores Lopez-Terrada
Baylor College of Medicine
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Angshumoy Roy
Texas Children's Hospital
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Donald Parsons
Baylor College of Medicine
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Abstract

Background: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically-annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. Methods: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next generation sequencing (NGS) library preparation using a custom 124 gene hybridization capture panel and the 75 gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. Results: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n=6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n=8), NTRK3 (n=4), and BRAF. Mutually-exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association (ATA) risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. Conclusions: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion positive tumors were more likely to have features of high-risk disease.
03 Jun 2020Submission Checks Completed
03 Jun 2020Assigned to Editor
03 Jun 2020Submitted to Pediatric Blood & Cancer
05 Jun 2020Reviewer(s) Assigned
10 Jul 2020Review(s) Completed, Editorial Evaluation Pending
27 Jul 2020Editorial Decision: Revise Minor
07 Aug 2020Submission Checks Completed
07 Aug 2020Assigned to Editor
07 Aug 20201st Revision Received
09 Aug 2020Reviewer(s) Assigned
08 Sep 2020Review(s) Completed, Editorial Evaluation Pending
10 Sep 2020Editorial Decision: Accept
Jan 2021Published in Pediatric Blood & Cancer volume 68 issue 1. 10.1002/pbc.28741