Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China.
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Thyroid. 2019 Oct;29(10):1447-1456. doi: 10.1089/thy.2018.0385. Epub 2019 Sep 11.
Inherited medullary thyroid carcinoma (MTC) is primarily caused by mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the proto-oncogene. Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline S409Y (c.1226 C>A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and/or thyroid surgery. Furthermore, analyses and assays were performed to predict or verify the potential oncogenic activity of the S409Y variant. Overall, 15 of 31 participants were found to carry the S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41-75 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41-76 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14-52 years) exhibited typical Ctn/sCtn levels ( < 0.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease. analyses revealed that S409Y was a "possibly damaging" mutation that could affect the RET protein inter-domain interface. An assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the C618Y and C634Y mutations. This study demonstrates that the novel germline S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, "at-risk" family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.
遗传性髓样甲状腺癌（MTC）主要由突变引起，这些突变通常定位于外显子 5、8、10、11 和 13-16。在本研究中，我们报告了携带有 MTC 的个体家系，这些个体携带有 原癌基因中的胚系 S409Y 变异。靶向测序用于诊断 4 例明显散发的 MTC 指数病例，这些病例携带有胚系 S409Y（c.1226 C>A）变异。随后，对这些个体的 27 名亲属进行了临床和遗传评估和/或甲状腺手术。此外，还进行了分析和测定，以预测或验证 S409Y 变异的潜在致癌活性。总的来说，在 31 名参与者中有 15 名携带 S409Y 变异。其中，6 名患有孤立性 MTC（平均年龄 50.2 岁；范围 41-75 岁），其中 3 名患有颈部淋巴结转移，2 名患有远处肝或肺转移。在其余 9 名携带者中，3 名（平均年龄 56 岁；范围 41-76 岁）血清钙刺激降钙素（sCtn）升高或同时血清降钙素（Ctn）水平升高，而另外 6 名（平均年龄 37.5 岁；范围 14-52 岁）表现出典型的 Ctn/sCtn 水平（ < 0.05）。这 4 个家系中的 15 名携带者均无嗜铬细胞瘤、甲状旁腺功能亢进或先天性巨结肠的临床证据。分析表明，S409Y 是一种“可能具有破坏性”的突变，可能影响 RET 蛋白的结构域间界面。测定表明，RET 酪氨酸 905 的磷酸化水平在 S409Y 突变体中比在野生型（WT）RET 中相对较高。此外，与 WT RET 相比，用 S409Y 转染 HEK 293 细胞可增强 AKT、ERK 通路的磷酸化活性，并增加细胞增殖，但程度低于 C618Y 和 C634Y 突变。本研究表明，新型胚系 S409Y 变异可能具有致病性，并与 C618Y 和 C634Y 突变相比，MTC 的外显率较低。S409Y 个体应采用个体化方法进行管理，此外，还应评估“高危”家庭成员。需要进一步研究来阐明 S409Y 突变与 2 型多发性内分泌肿瘤特异性肿瘤之间的相关性。
