Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Abstract

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age

“…Our findings, therefore, provide somewhat counterintuitive yet robust evidence that, in young patients, the BRAF V600E -positive tumors, which are characterized by the higher Ki67 LI and smaller size, do not display a more aggressive phenotype. These results are in line with several previous reports of the lack of overly aggressive features in the BRAF V600E -positive PTC in pediatric patients [ 17 , 24 , 49 , 50 , 51 , 52 , 53 ].…”

“…Of importance, however, the frequency of BRAF V600E remains consistently higher in sporadic PTCs as compared to radiogenic PTCs in all age subgroups. The latter observation is in line with a recent report on molecular findings in childhood PTC from Belarus [ 17 ].…”

“…The radiogenic PTCs, especially those detected after the shorter latency, had a very high frequency of RET/PTC3 rearrangements, which is associated with more aggressive tumor phenotype and a solid-trabecular growth pattern [ 5 , 6 , 7 , 8 , 56 , 57 ]. The frequency of RET/PTC3 is lower in sporadic PTC, even from young children, and other types of activated oncogenes do not seem to confer very high tumor aggressiveness in young patients [ 17 , 58 ].…”

“…In sporadic pediatric PTC, BRAF V600E was not detected in a small group of non-exposed children from Ukraine [ 15 ]. However, more recent works reported BRAF V600E in about one-fourth of non-exposed children and adolescents with PTC [ 10 , 17 ]. Each of these studies had certain strengths and limitations; the latter mostly due to the relatively small sample sizes and frequent unavailability of the appropriate control groups.…”

The Prognostic Significance of BRAF Gene Analysis in Children and Adolescents with Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

“… BRAF mutation and Gender correlation forest plot [ 7 , 12 , 14 , 15 , 16 , 17 , 18 , 20 , 24 , 25 , 26 , 28 , 30 , 31 , 33 , 37 , 38 , 40 , 42 , 43 , 45 , 47 , 48 , 49 ]. …”