儿童及年轻成人甲状腺结节中的DICER1变异

背景：近期研究表明，DICER1基因的致病变异可能驱动部分儿科甲状腺结节的变化，但相关数据仍有限。本研究旨在在大规模儿科甲状腺结节队列中检测DICER1基因的变异，并结合临床病理数据，重点关注甲状腺癌患者的疾病预后。方法：这是一项回顾性队列研究，包含350名年龄在2-21岁的儿科及年轻成人甲状腺结节患者，采集了275份新鲜冷冻样本和92份细针穿刺活检（FNAB）样本。通过下一代测序和多重连接探针扩增技术检测甲状腺肿瘤主要遗传变异中的DICER1突变。对DICER1阳性患者的外周血进行分析。将遗传分析结果与临床病理资料进行相关性分析。结果：在350名患者中，检测到DICER1基因变异的有24名（6.9%；95%置信区间[CI]，[4.4-10.0]），其中在良性冷冻组织中为10/119（8.4%；[4.1-14.9]），乳头状甲状腺癌（PTC）中为8/141（5.7%；[1.9-9.5]），FNAB样本中为6/86（7.0%；[4.1-14.6]）。未在DICER1阳性样本中发现其他基因变异。血源性DICER1变异在11/24（45.8%；[25.6-67.2]）患者中检测到。9/24（37.5%；[18.8-59.4]）的甲状腺结节存在两个体细胞（双等位基因）变异。2/24（8.3%；[1.0-27.0]）病例发现长达3Mbp以上的体细胞缺失。DICER1阳性的PTC显著与滤泡亚型（p=0.001）、包裹（p=0.006）相关，且腺瘤体积较大（p=0.035），但无甲状腺外扩（p=0.039），淋巴结转移较少（p=0.003）。DICER1阳性患者对治疗反应良好，75%的患者获得了优异的疗效。结论：DICER1基因变异在儿科及年轻成人甲状腺结节中较为常见。DICER1阳性的PTC表现出低侵袭性。我们的研究支持对DICER1阳性低风险PTC采取更保守的治疗策略。

Background: Recent studies have suggested that pathogenic variants of the DICER1 gene could be a driver of alterations in some pediatric thyroid nodules, but data are still limited. The aim of this study was to detect variants in the DICER1 gene in a large cohort of pediatric thyroid nodules and then correlate them with clinicopathological data, with a focus on the disease prognosis in patients with thyroid carcinoma. Methods: This retrospective cohort study consisted of 350 pediatric and young adult patients (aged 2-21 years) with thyroid nodules, from whom 275 fresh-frozen thyroid nodule samples and 92 fine-needle aspiration biopsy (FNAB) samples were collected. After an analysis of variants in major genetic alterations of thyroid tumors, variants in the DICER1 gene were identified using next-generation sequencing and multiplex ligation-dependent probe amplification methods. Peripheral blood was analyzed from patients with DICER1-positive tumors. The results of genetic analysis were then correlated with clinicopathological data. Results: Variants in the DICER1 gene were detected in a total of 24/350 (6.9%; 95%CI [4.4;10.0]) pediatric and young adult patients, respectively, in 10/119 (8.4%; [4.1;14.9]) patients with benign fresh-frozen tissue, in 8/141 (5.7%; [1.9;9.5]) with papillary thyroid carcinoma (PTC) and in 6/86 (7.0%; [4.1;14.6]) patients with FNAB. No other gene alteration was found in DICER1-positive samples. Germline DICER1 variants were identified in 11/24 (45.8%; [25.6;67.2]) patients. Two somatic (biallelic) variants in the DICER1 gene were found in 9/24 (37.5%; [18.8;59.4]) thyroid nodules. Somatic deletions of at least 3 Mbp long were revealed in 2/24 (8.3%; [1.0;27.0]) cases. DICER1-positive PTCs were significantly associated with the follicular subtype of PTC (p = 0.001), encapsulation (p = 0.006) and were larger in size (p = 0.035), but with no extrathyroidal extension (p = 0.039), and less frequent lymph node metastases (p = 0.003) compared with DICER1-negative PTCs. Patients with DICER1-positive PTC had an excellent response to treatment in 75% of cases. Conclusions: Variants of the DICER1 gene are frequently found in the thyroid nodules of pediatric and young adult patients. In our patients, DICER1-positive PTCs showed low invasiveness. Our findings support considering more conservative management for DICER1-positive low-risk PTCs.