Endocrine Abstracts

Objectives: Pathogenic variants in the DICER1 gene can be found in both benign and malignant thyroid nodules, more often in pediatric patients. Somatic pathogenic variants in "hotspot" regions can coexist with germline variants in other regions of the DICER1 gene, which are associated with DICER1 syndrome, an autosomal dominantly inherited disease that predisposes to the development of various tumors from childhood. In addition to thyroid tumors, pleuropulmonary blastoma, pediatric cystic nephroma and other tumors can develop. The aim of the work was to detect variants in the DICER1 gene in a large group of pediatric patients with thyroid nodules.

Methods: The study consisted of two cohorts - fresh frozen thyroid tissue samples from 239 patients and samples collected by fine needle aspiration biopsy (FNAB) from 78 patients; both aged 2-20 years. In case of positive findings, peripheral blood was determined. Extracted DNA was used for next-generation sequencing on MiSeq sequencer (Illumina) using the Nextera XT DNA Library Prep Kit (Illumina). Mutations in the DICER1 gene were visualized in Integrative Genomics Viewer (Broad Institute) and evaluated by the VarSome platform (Saphetor SA).

Results: Pathogenic DICER1 hotspot mutations were detected in 13 of 239 (5.4%) fresh frozen pediatric thyroid tissues including 6 papillary thyroid carcinomas (PTCs), 1 low-risk tumor, 6 benign nodules. Additional mutation in the DICER1 gene was found in 8 of them. There were 4 patients with tumor-specific biallelic DICER1 mutation, who, according to available studies, are risk-free of other tumors associated with DICER1 syndrome. Four patients with germline variants were classified as individuals with DICER1 syndrome. Patients with PTCs had no lymph metastasis and had excellent response to the treatment. In the cohort of FNAB samples, 6 (7.7%) DICER1- positive samples were detected (cytologically evaluated as 3x Bethesda II, 2x Bethesda IV, 1x Bethesda VI). Two patients had second germline pathogenic DICER1 variant and one had another somatic variant. A total of 4/6 patients had already undergone surgery - samples were histologically evaluated as nodular goiters and one as follicular carcinoma.

Conclusions: In summary, DICER1 variants are important molecular markers in pediatric thyroid nodules. In the case of positive finding, it is also necessary to exclude germinal origin of detected variants. Although the penetrance of DICER1 syndrome is incomplete, regular follow-up of these individuals and their relatives according to surveillance recommendations is very important for earlier detection of additional tumors.Supported by AZV NU21-01-00448 and MH CZ RVO 00023761.