小儿和年轻成人甲状腺结节的DICER1变体

背景：最近的研究表明，DICER1基因的致病变异可能是某些儿科甲状腺结节改变的驱动力，但数据仍然有限。这项研究的目的是检测大量小儿甲状腺结节中DICER1基因中的变异，然后将它们与临床病理学数据相关联，重点是甲状腺癌患者的疾病预后。方法：这项回顾性队列研究包括350例儿科和年轻患者（2-21岁）和甲状腺结节，从中收集了275种新鲜富型甲状腺结节样品，并收集了92个细节样品。在分析了甲状腺肿瘤的主要遗传改变中的变体后，使用下一代测序和多重连接依赖性探针扩增方法鉴定了DICER1基因中的变体。对DICER1阳性肿瘤患者的外周血进行了分析。然后将遗传分析的结果与临床病理学数据相关。结果：在总共24/350（6.9％； 95％CI [4.4; 10.0]）的儿科和年轻人患者中，在10/119（8.4％; [4.1; 14.9]）患者的良性新鲜粉丝组织患者中，分别检测到DICER1基因的变异。 （PTC）和6/86（7.0％; [4.1; 14.6]）FNAB患者。在DICER1阳性样品中未发现其他基因改变。在11/24（45.8％; [25.6; 67.2]）患者中鉴定出种系DICER1变体。在9/24（37.5％; [18.8; 59.4]）甲状腺结节中发现了DICER1基因中的两个体细胞（双重）变体。在2/24（8.3％; [1.0; 27.0]）病例中揭示了至少3 Mbp的体细胞缺失。 DICER1阳性PTC与PTC（P = 0.001），封装（P = 0.006）的卵泡亚型显着相关，大小较大（P = 0.035）（P = 0.035），但没有手甲外延伸（P = 0.039），频率较低，频率较低的淋巴结式变形（PTC）与PTS相比（P = 0.003）。 DICER1阳性PTC患者在75％的病例中对治疗的反应很好。结论：DICER1基因的变体经常在小儿和年轻患者的甲状腺结节中发现。在我们的患者中，DICER1阳性PTC的侵入性低。我们的发现支持考虑对DICER1阳性低风险PTC的更多保守管理。

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.