背景 甲状腺恶性肿瘤的诊断分类主要通过组织形态学特征的检查来完成，并且可以通过分子数据证实和澄清。各个分子驱动因素与甲状腺恶性肿瘤的组织学亚型表现出相对强健和特定的关联，包括甲状腺乳头状癌中的 BRAF 序列变异和激酶基因融合，滤泡型肿瘤中主要是 RAS 变异，以及影响 TERT 启动子 TP53 的其他“晚期”突变，以及高级别恶性肿瘤中的 PI3K/AKT/PTEN 通路。鉴于 FGFR，特别是 FGFR1-3 的致癌作用，本研究的目的是探讨 FGFR 在甲状腺癌生物学中的作用。方法 我们完成了一项针对 FGFR 基因家族致病性改变的甲状腺癌的多中心回顾性观察研究。我们通过查询每个中心积累的甲状腺癌分子数据来进行这项研究。结果 总体而言，对 5,030 例已测序的甲状腺恶性肿瘤进行了审查，产生了 17 例具有 FGFR 改变的肿瘤，其中 11 例 FGFR 是主要分子驱动因素，6 例 FGFR 是次要致病性改变，其中一个子集有可用的临床随访数据。在具有 FGFR 驱动的 11 种癌症中，9 种是涉及 FGFR2::VCL（4 个肿瘤）、TG::FGFR1（3 个肿瘤）、FGFR2::CIT 和 FGFR2::SHTN1 的基因融合，其余 2 个由 FGFR2::SHTN1 驱动。 FGFR1 扩增。在存在甲状腺肿瘤典型驱动因素（5 例）或未检测到明确的主要驱动因素（1 例）的 6 个肿瘤中，测序检测到继发性 FGFR2 p.W290C、p.Y375C 和 p.N549K 以及 FGFR1 p.N546K 位于各自的酪氨酸激酶结构域中，其中一些处于亚克隆变异等位基因频率。结论 本研究首次描述了按 FGFR 主要驱动因素变化分组的甲状腺癌集合，以及具有可能导致肿瘤进展或对靶向治疗产生耐药性的继发性变化的甲状腺肿瘤队列。鉴于针对致癌性 FGFR 的小分子抑制剂的可用性，本研究强调了识别 FGFR 改变对患者的重大影响，因为这些改变目前在文献中尚未得到充分认识，最重要的是，它们具有潜在的新颖治疗选择。

Background Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods We completed a multi-center retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results Overall, 5,030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2::VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.