Cabral Miranda Lara Judith, Danilovic Débora L S, Vanderlei Felipe Augusto Brasileiro, Tavares Marcos Roberto, Neto Nicolau Lima, Asato de Camargo Rosalinda Yossie, Marui Suemi
Laboratório de Endocrinologia Celular e Molecular (LIM25), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
Unidade de Tireoide, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
Arch Endocrinol Metab. 2024 Feb 8;68:e230030. doi: 10.20945/2359-4292-2023-0030.
Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG.
Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed.
Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels.
We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development.
在分化型甲状腺癌（DTC）和多结节性甲状腺肿（MNG）中发现DICER1突变，其发病年龄较年轻，常伴有其他肿瘤，这是DICER1综合征的特征。DICER1是DTC的驱动因素之一；然而，在良性结节中也能发现它。我们推测，DICER1突变患者可能表现为长期存在的MNG。我们的目的是调查MNG患者中DICER1变异的频率。
对因有症状的巨大MNG而接受全甲状腺切除术的患者进行评估。对甲状腺结节样本进行DICER1热点区域测序。为确认体细胞突变，还对外周血DNA进行了分析。
在715例患者中，154例接受了评估，年龄为56.2±12.3岁（28 - 79岁），甲状腺体积为115.7±108 mL（16.2 - 730）。我们发现11%的患者存在6种处于纯合或杂合状态的DICER1变异。只有rs12018992是体细胞DICER1变异。根据ClinVar数据库，其余所有变异都是同义的，可能为良性。rs12018992此前在一名患有13 mm DTC的青少年中被描述过。DICER1携带者在性别、甲状腺肿家族史、年龄、甲状腺体积、促甲状腺激素（TSH）和甲状腺影像报告和数据系统（TI-RADS）分类方面无显著差异。无论TSH水平如何，DICER1基因多态性患者的游离甲状腺素（Free T4）较低（13.77±1.8 vs. 15.44±2.4 pmol/L，p = 0.008）。
我们得出结论，在11%的巨大甲状腺肿中可发现种系DICER1变异，但未发现二次打击体细胞突变。DICER1是甲状腺病变的驱动因素之一，在MNG发展过程中似乎不需要二次打击事件。
