loading page

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma
  • +16
  • 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
Author Profile
Jacquelyn Reuther
Baylor College of Medicine
Author Profile
Raghu Chandramohan
Baylor College of Medicine
Author Profile
Ilavarasi Gandhi
Baylor College of Medicine
Author Profile
Faith Hollingsworth
Baylor College of Medicine
Author Profile
Hadi Sayeed
Texas Children's Hospital
Author Profile
Horatiu Voicu
Texas Children's Hospital
Author Profile
Nipun Kakkar
Texas Children's Cancer Center
Author Profile
Koel Sen Baksi
Texas Children's Cancer Center
Author Profile
Stephen Sarabia
Baylor College of Medicine
Author Profile
Monica Lopez
Texas Children's Hospital
Author Profile
Daniel Chelius
Texas Children's Hospital
Author Profile
Ioanna Athanassaki
Baylor College of Medicine
Author Profile
Priya Mahajan
Texas Children's Cancer Center
Author Profile
Rajkumar Venkatramani
Texas Children's Hospital
Author Profile
Norma Quintanilla
Texas Children's Hospital
Author Profile
Dolores Lopez-Terrada
Baylor College of Medicine
Author Profile
Angshumoy Roy
Texas Children's Hospital
Author Profile
Donald Parsons
Baylor College of Medicine
Author Profile

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.

Peer review status:ACCEPTED

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