{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:23:02Z","timestamp":1776424982525,"version":"3.51.2"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Pathology &amp; Laboratory Medicine at the University of Kentucky College of Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt\u2013Hogg\u2013Dub\u00e9 (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations\u2014one germline and one somatic\u2014and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN\u2019s role in thyroid cancer pathogenesis.<\/jats:p>","DOI":"10.3390\/curroncol32040224","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T10:05:51Z","timestamp":1744365951000},"page":"224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration"],"prefix":"10.3390","volume":"32","author":[{"given":"Faisal A.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0300-3544","authenticated-orcid":false,"given":"Camryn","family":"Slone","sequence":"additional","affiliation":[{"name":"Kentucky College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie C.","family":"Dueber","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeel M.","family":"Ashraf","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melina J.","family":"Windon","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver J.","family":"Fackelmayer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Endocrine Surgery, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cortney Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Endocrine Surgery, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0899-9405","authenticated-orcid":false,"given":"Therese J.","family":"Bocklage","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"},{"name":"Markey Cancer Center, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5119-2474","authenticated-orcid":false,"given":"Derek B.","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40506, USA"},{"name":"Markey Cancer Center, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s12022-020-09661-y","article-title":"Inherited follicular epithelial-derived thyroid carcinomas: From molecular biology to histological correlates","volume":"32","author":"Mete","year":"2021","journal-title":"Endocr. 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