Dataset Information

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.

SUBMITTER: Picarsic JL

PROVIDER: S-EPMC5894824 | biostudies-literature | 2016 Mar-Apr

REPOSITORIES: biostudies-literature

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Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.

Picarsic Jennifer L JL Buryk Melissa A MA Ozolek John J Ranganathan Sarangarajan S Monaco Sara E SE Simons Jeffrey P JP Witchel Selma F SF Gurtunca Nursen N Joyce Judith J Zhong Shan S Nikiforova Marina N MN Nikiforov Yuri E YE

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 20150914 2

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. Th ...[more]

PMID: 26367451

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Project description:BACKGROUND:Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules. METHODS:The evaluation of 143 consecutive FNA samples with a cytologic diagnosis of FN/SFN from patients with known surgical outcomes included 91 retrospective samples and 52 prospective samples. Analyses were performed on a proprietary sequencer using the targeted ThyroSeq v2 NGS panel, which simultaneously tests for point mutations in 13 genes and for 42 types of gene fusions that occur in thyroid cancer. The expression of 8 genes was used to assess the cellular composition of FNA samples. RESULTS:In the entire cohort, histologic analysis revealed 104 benign nodules and 39 malignant nodules. The most common point mutations involved the neuroblastoma RAS viral oncogene homolog (NRAS), followed by the Kirsten rat sarcoma viral oncogene homolog (KRAS), the telomerase reverse transcriptase (TERT) gene, and the thyroid-stimulating hormone receptor (TSHR) gene. The identified fusions involved the thyroid adenoma associated (THADA) gene; the peroxisome proliferator-activated receptor ? (PPARG) gene; and the neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) gene. Performance characteristics were similar in the retrospective and prospective groups. Among all FN/SFN nodules, preoperative ThyroSeq v2 performed with 90% sensitivity (95% confidence interval [CI], 80%-99%), 93% specificity (95% CI, 88%-98%), a positive predictive value of 83% (95% CI, 72%-95%), a negative predictive value of 96% (95% CI, 92%-100%), and 92% accuracy (95% CI, 88%-97%). CONCLUSIONS:The current results indicate that comprehensive genotyping of thyroid nodules using a broad NGS panel provides a highly accurate diagnosis for nodules with FN/SFN cytology and should facilitate the optimal management of these patients.

Project description:IntroductionSepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting.MethodsThe Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1-d28, n = 50), infants (d29 to <1 yr, n = 50), and toddlers (1 yr to <5 yr, n = 50) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definition) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard of care (culture-based) microbiological diagnostics. Potential changes in anti-infective treatment regimens based on these NGS results will be estimated retrospectively by a panel of 3 independent clinical specialists.DiscussionNeonates, infants, and young children are significantly affected by sepsis. Fast and more sensitive diagnostic approaches are urgently needed. This prospective, observational, non-interventional, multicenter study seeks to evaluate an NGS-based approach in critically ill children suffering from sepsis.Trial registrationDRKS-ID: DRKS00015705 (registered October 24, 2018). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015705.

Dataset Information

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.

Publications

Molecular Characterization of Sporadic Pediatric Thyroid Carcinoma with the DNA/RNA ThyroSeq v2 Next-Generation Sequencing Assay.

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