Predominant DICER1 Pathogenic Variants in Pediatric Follicular Thyroid Carcinomas.

Abstract

Background: Pediatric thyroid cancer has characteristics that are distinct from adulthood thyroid cancer. Due to its very low prevalence, little is known about the genetic characteristics of pediatric follicular thyroid cancer (FTC). Methods: We investigated genetic alterations in tumor tissues from 15 patients aged <20 years (median: 14.3 years; range: 2.4 - 19.0 years) using multifaceted approaches. Whole-exome sequencing, targeted next-generation sequencing using a cancer gene panel, and Sanger sequencing of the major exons of the H/K/N-RAS and DICER1 genes and the promoter region of the TERT gene were performed. Normal tissues or blood of patients with DICER1- or PTEN-positive tumors was also evaluated to determine whether the variant is germ line. Results: The median tumor size was 3.1 cm (range: 0.6 - 6.4 cm). Four patients exhibited angioinvasion and one extensive capsular invasion; none showed evidence of disease over a median of 8.1 years. Eight patients (53.3%) had DICER1 variants, including four with DICER1 syndrome (three patients were <10 years of age). One patient had a germ line PTEN frameshift variant with the diagnosis of PTEN hamartoma tumor syndrome. One patient had a PAX8/PPARγ rearrangement, and two patients had no genetic driver alteration other than multiple loss of heterozygosity with or without copy number alterations in their tumors. No RAS or TERT variants were found. Nodular hyperplasia and follicular adenoma (FA) coexisted in DICER1 variant-positive FTCs more frequently than variant-negative FTCs (p = 0.026). All DICER1 variant-positive FTCs had a somatic missense variant at metal binding sites (six at codon p.E1813 and two at codon p.D1709) within the RNase IIIb domain; seven had other missense, nonsense, or frameshift variants in the DICER1 gene. Six coexisting FAs of two patients with DICER1 syndrome (three of each) had additional somatic variants at metal binding sites within the RNase IIIb domain (codon p.E1705, p.D1709, p.D1810, or p.E1813), different from each other and from the indexed FTC tumor. Conclusions: Pediatric FTCs have distinct genomic alterations and pathogenesis compared with adults, particularly those characterized by DICER1 variants. The DICER1 variant should be considered in pediatric FTCs, especially in cases <10 years of age. In all DICER1 variant-positive FTCs and FAs, recurrent hotspot variants were found at metal binding sites within the RNase IIIb domain, suggesting they impact tumorigenesis.