Abstract：
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 multicenter 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, 5030 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.
摘要：
背景技术甲状腺恶性肿瘤的诊断分类主要通过检查组织形态学特征来完成,并且可以通过分子数据来证实和澄清。个体分子驱动因子与甲状腺恶性肿瘤的组织学亚型表现出相对稳健和特异性的关联，包括BRAF序列变异和激酶基因融合在甲状腺乳头状癌中，主要是滤泡样肿瘤中的RAS变异，以及影响TERT启动子的其他“晚期”突变，TP53和高级别恶性肿瘤中的PI3K/AKT/PTEN通路。鉴于FGFR的致癌作用，特别是FGFR1-3,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FGFR基因家族致病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。总体结果,5,030测序的甲状腺恶性肿瘤进行了回顾，产生17个FGFR改变的肿瘤，包括11个FGFR是主要的分子驱动因素，6个FGFR是次要的致病因素，与有可用的临床随访数据的子集。在有FGFR驱动的11个癌中，9个是涉及FGFR2::VCL（4个肿瘤）的基因融合，TG：：FGFR1（3个肿瘤），FGFR2::CIT,和FGFR2::SHTN1,其余2个由FGFR1扩增驱动。在6个肿瘤中，存在甲状腺瘤变的典型驱动因素（5例）或未检测到明确的主要驱动因素（1例），测序检测到二级FGFR2p.W290C，p.Y375C,和p.N549K，以及各自酪氨酸激酶结构域中的FGFR1p.N546K，一些处于亚克隆变异等位基因频率。结论这项研究首次描述了甲状腺癌的集合，这些甲状腺癌按FGFR的主要驱动因素改变进行分组，以及一组可能导致肿瘤进展或对靶向治疗耐药的继发性改变的甲状腺肿瘤。鉴于靶向致癌FGFR的小分子抑制剂的可用性，这项研究强调了FGFR改变的识别对患者的重要意义，因为它们目前在文献中被低估了，最重要的是,有潜在的新治疗选择。
