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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Single Point Mutations in Pediatric Differentiated Thyroid Cancer
Ali S Alzahrani1,2, Avaniyapuram Kannan Murugan2, Ebtesam Qasem2
11 Department of Medicine, King Faisal Specialist Hospital and Research Centre , Riyadh, Saudi Arabia .
Purpose:
Differentiated thyroid cancer (DTC) is rare in children. Previous studies have suggested that it has different clinicopathologic features and mutation profiles compared with adult DTC. However, those studies focused on a single or limited number of gene mutations. This study comprehensively investigated a large series of pediatric DTC for single point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, PTEN, and TERT. It also analyzed associations between clinicopathologic features and the BRAFV600E mutation.
Patients And Methods:
Eighty-nine consecutive cases seen in children and adolescents (≤18 years) during 1998-2015 were identified. Rare variants of DTC were excluded, and the study focused on 72 (91.1%) classical papillary thyroid carcinoma (PTC) and seven (8.9%) follicular variant PTC. These included 68 (86.1%) females and 11 (13.9%) males, with a median age of 15.5 years (range 8-18 years). The clinical and histopathological data were obtained from medical records. DNA was extracted from paraffin-embedded tumor tissue, and was PCR-amplified and directly sequenced.
Results:
Mutations detected included BRAFV600E in 19/72 (26.4%) classical PTC samples, and in none of seven follicular variant PTC. Other mutations included: 1/78 (1.3%) successfully amplified tumor samples with TERT C228T; 2/79 (2.5%) NRAS 61 (c.181C>A and c.182A>G); 1/73 (1.4%) PIK3CA exon 9 (c.1589A>G and c.1598C>T in one tumor); 1/79 (1.3%) PIK3CA exon 20 (c.2951G>A); and 1/74 (1.4%) PTEN exon 5 (c.295G>A). No mutation was found in HRAS, KRAS, NRAS12, PTEN exons 6, 7, and 8, and TERT C250T. No significant association was found between BRAFV600E mutation and sex, extrathyroidal invasion, tumor multifocality, vascular invasion, lymph node or distant metastases, and persistent/recurrent disease.
Conclusions:
In pediatric DTC, the prevalence of the BRAFV600E mutation is significantly less common compared with adult DTC, and there is no association between this mutation and the histopathological features and outcome of PTC. PIK3CA, PTEN, NRAS 61, and TERT C228T mutations are rare.
Insights
Pediatric differentiated thyroid cancer (DTC) shows a lower prevalence of the BRAFV600E mutation compared to adults. This mutation was not associated with histopathological features or outcomes in pediatric papillary thyroid carcinoma (PTC).
Area of Science:
- Oncology
- Genetics
- Pediatric Medicine
Background:
- Differentiated thyroid cancer (DTC) is uncommon in children, with distinct clinicopathologic features and mutation profiles compared to adult DTC.
- Previous research on pediatric DTC mutations was limited to single or a few gene analyses.
- Comprehensive genetic profiling is needed to understand the molecular landscape of pediatric DTC.
Purpose of the Study:
- To investigate single point mutations in key genes (BRAF, HRAS, KRAS, NRAS, PIK3CA, PTEN, TERT) in a large cohort of pediatric DTC.
- To analyze the association between the BRAFV600E mutation and clinicopathologic features in pediatric DTC.
- To compare mutation profiles in pediatric DTC with those reported in adult DTC.
Main Methods:
- Analysis of 89 pediatric DTC cases (≤18 years) diagnosed between 1998-2015, focusing on 72 classical PTC and 7 follicular variant PTC.
- DNA extraction from tumor tissue, followed by PCR amplification and direct sequencing for mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, PTEN, and TERT.
- Correlation of BRAFV600E mutation status with clinical and histopathological data, including sex, invasion, multifocality, metastasis, and disease persistence.
Main Results:
- BRAFV600E mutation was detected in 26.4% of classical PTC cases, significantly lower than in adult DTC.
- Other detected mutations included rare instances of TERT C228T, NRAS 61, PIK3CA (exons 9 and 20), and PTEN exon 5.
- No significant association was found between BRAFV600E and clinicopathological features or patient outcomes.
Conclusions:
- The BRAFV600E mutation is less prevalent in pediatric DTC compared to adult DTC and does not correlate with histopathological characteristics or prognosis.
- Mutations in PIK3CA, PTEN, NRAS 61, and TERT C228T are infrequent in pediatric DTC.
- These findings highlight genetic differences between pediatric and adult DTC, underscoring the need for distinct diagnostic and therapeutic approaches.
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