Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
J Clin Endocrinol Metab. 2018 May 1;103(5):2009-2015. doi: 10.1210/jc.2017-02698.
Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma.
In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations.
Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected.
The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1.
Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations.
DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens.
甲状腺乳头状癌（PTC）是青少年中常见的恶性肿瘤，在分子和临床方面与成人 PTC 不同。DICER1 基因突变与甲状腺异常有关，包括多结节性甲状腺肿和分化型甲状腺癌。
本研究旨在探讨 DICER1 变异在儿科 PTC 中的流行情况，特别是在无传统 PTC 致癌改变的肿瘤中。
选择了 40 名接受部分或全甲状腺切除术且手术时年龄<18 岁的患者。
对 40 例连续甲状腺切除术标本（30 例恶性，10 例良性）进行了 17 种与 PTC 相关的变异体的基因分型，以及 DICER1 的外显子和外显子-内含子边界的全序列分析。
在 30 例 PTC 中有 12 例（40%）发现了常规改变（5 例 BRAFV600E，3 例 RET/PTC1，4 例 RET/PTC3）。在 30 例中的 3 例（10%）PTC 和 10 例中的 2 例（20%）良性结节中发现了致病性 DICER1 变异体，这些结节均缺乏常规改变，且在随访期间未复发。因此，在无常规改变的 18 例 PTC 中有 3 例（16.7%）为 DICER1 改变。这 3 例 DICER1 突变癌各自有两个体细胞 DICER1 改变，而两个滤泡状结节性病变发生在有胚系 DICER1 突变的患者中，并具有特征性的第二个体细胞 RNase IIIb“热点”突变。
DICER1 是儿童甲状腺结节的驱动因素，DICER1 突变的 PTC 可能代表一类独特的低风险恶性肿瘤。鉴于儿童中变异体的流行，我们主张在儿童甲状腺标本的分子分析中纳入 DICER1 测序和基因剂量测定。
