<i>Folliculin</i> (<i>FLCN</i>) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration
Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (<i>FLCN</i>), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic <i&g...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Current Oncology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1718-7729/32/4/224 |
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| Summary: | Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (<i>FLCN</i>), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic <i>FLCN</i> alterations—one germline and one somatic—and analyze the broader prevalence and significance of <i>FLCN</i> in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline <i>FLCN</i> mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic <i>FLCN</i> inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic <i>FLCN</i> 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 <i>FLCN</i> 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 <i>FLCN</i> mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of <i>FLCN</i> coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including <i>FLCN</i> 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 <i>FLCN</i>’s role in thyroid cancer pathogenesis. |
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| ISSN: | 1198-0052 1718-7729 |