<i>FGFR</i> Alterations in Thyroid Carcinoma: A Novel Class of Primary Drivers with Significant Therapeutic Implications and Secondary Molecular Events Potentially Mediating Resistance in Thyroid Malignancy

<b><i>Background:</i></b> 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 <i>BRAF</i> sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly <i>RAS</i> variants in follicular-patterned neoplasia, and additional "late" mutations affecting <i>TERT</i> promoter, <i>TP53</i>, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of <i>FGFR</i>, particularly <i>FGFR1-3</i>, the goal of this study was to explore the role of <i>FGFR</i> in thyroid carcinoma biology. <b><i>Methods:</i></b> We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the <i>FGFR</i> gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. <b><i>Results:</i></b> Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with <i>FGFR</i> alterations, including 11 where <i>FGFR</i> was the primary molecular driver and 6 where <i>FGFR</i> was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an <i>FGFR</i> driver, 9 were gene fusions involving <i>FGFR2:VCL</i> (4 tumors), <i>TG::FGFR1</i> (3 tumors), <i>FGFR2::CIT</i>, and <i>FGFR2::SHTN1</i>, and the remaining 2 were driven by <i>FGFR1</i> 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 <i>FGFR2</i> p.W290C, p.Y375C, and p.N549K, as well as <i>FGFR1</i> p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. <b><i>Conclusions:</i></b> This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in <i>FGFR</i>, 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 <i>FGFR</i>, this study emphasizes the significant implications for patients from identification of <i>FGFR</i> alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.